/' 


Columbia  Wini\itt^itp 
in  ttje  €itp  of  ileto  |?ork 

College  of  ^i)j>s(icians;  antr  burgeons; 


l^eference  Xibrarp 


THE    PHYSIOLOGY   OF   DIGESTION. 


,■1,1  VI 

MERCERS'  COMPANY  LECTURES 

ON 

RECENT    ADVANCES 

IN  THE 

PHYSIOLOGY  OF  DIGESTION 

Delivered   in  the  Michaelmas  Term,  1905,  in  the 

Physiological  Department  of  University 

College,  London. 


BY 

ERNEST    H.   STARLING,  M.D.,  F.R.S., 

jodrell  professor  of  physiology. 


WITH   TWELVE  ILLUSTRATIONS. 


CHICAGO : 
W.    T.   KEENEE  &   CO. 
1906. 


d»4— *■ 


PREFACE. 


In  recognition  of  a  generous  gift  by  the  Mercers'  Company 
in  aid  of  the  work  of  the  Physiological  Department  at  University 
College,  the  Council  of  the  College  resolved  that  a  course 
of  Lectures  should  be  given  each  year  dealing  with  the 
original  investigations  made  in  the  Department. 

In  presenting  this  first  course  of  Mercers'  Company  Lectures 
I  have  attempted,  in  the  light  of  researches  which  have  been 
carried  out  in  this  laboratory,  to  give  an  appreciation  of  the 
present  state  of  our  knowledge  on  certain  aspects  of  the 
subject  of  digestion,  in  preference  to  describing  at  length  the 
researches  themselves,  which  can  be  read  in  the  original  papers 
enumerated  at  the  end  of  this  book. 

The  great  development  in  this  branch  of  Physiology,  which 
has  taken  place  in  recent  years,  owes  its  inception  to  the 
masterly  series  of  researches  carried  out  by  Pawlow  in  the 
Institute  of  Experimental  Medicine  at  St.  Petersburg, 
researches  to  which  I  shall  have  repeated  occasion  to  refer  in 
the  course  of  the  following  Lectures.  Two  other  important 
lines  of  investigation  have  presented  themselves  as  necessary 
to  the  proper  understanding  of  the  biological  facts  elucidated  by 
Pawlow.  The  first  of  these  is  the  study  of  the  chemical  and 
physical  conditions  which  determine  the  digestive  changes  in 
the  food-stufis.  As  will  be  seen  in  the  first  two  Lectures,  we 
approach  here  a  subject  which  must  play  a  great  part  in  all  our 
future  conceptions  of  intracellular  mechanism,  i.e.,  the  study 


VI  PREFACE. 

of  chemical  and  physical  changes  in  capillary  and  colloidal 
systems,  where  the  modification  of  physical  condition  occurring 
at  sm-faces  determines  changes  of  quite  another  order  to  those 
which  have  so  far  formed  the  chief  pre-occupation  of  physics 
and  chemistry. 

The  second  line  had  its  starting  point  in  the  discovery  that 
the  pancreas  is  normally  excited  to  secrete,  in  response  to 
stimuli  originating  in  the  gut,  not,  as  Pawlow  thought,  by 
means  of  the  nervous  system,  but  by  the  dispatch  of  a  chemical 
messenger  or  hormone  from  the  seat  of  stimulation  to  the 
reacting  gland  through  the  blood-stream.  Subsequent 
investigations  have  shown  the  existence  of  other  chemical  cor- 
relations of  the  same  nature  and  suggest  that,  by  the  detection 
and  isolation  of  such  hormones,  we  may  later  be  in  a  position 
to  influence  and  control  a  number  of  the  chief  functions  of 
the  body. 

I  trust  that  the  publication  of  these  Lectures  may  serve  to 
interest  a  larger  audience  of  students  and  medical  men  in  the 
"  growing  border  "  of  these  important  subjects  and  to  give 
them  some  idea  of  the  aims  and  objects  of  this  branch  of 
physiological  research. 

EENEST   H.    STAELING. 

Physiological  Laboratory, 

University  College, 

March,  1906. 


CONTENTS. 


LECTrRE  PAGE 

I.      THE    FOOD-STUFFS  AND  THEIR  CHANGES  DURING  DIGES- 
TION— THE   3I0DE   OF  ACTION   OF   FERMENTS         .            .  1 

II.      THE   MODE   OF  ACTION  OF  FERMENTS   {contmueil)         .      .  20 

III.  SECRETION   OF   SALIVA 41 

IV.  DIGESTION   IN  THE   STOMACH 62 

V.      PANCREATIC   SECRETION 80 

VI.      CHANGES   IN   THE   PANCREAS   DURING   SECRETION        .      .  94 

VII.      THE   PROPERTIES  OF   THE  PANCREATIC  JUICE           .           .  102 

VIII.      THE   BILE 112 

IX.      THE   INTESTINAL  JUICE 120 

X.      THE   MOVEMENTS   OF   THE   ALIMENTARY   TRACT              .      .  129 


LIST    OF    ILLUSTRATIONS    AND 
DIAGRAMS. 

♦ 

FTOITRE.  p^,,j, 

"1.  DIAGRAM  SHOWING-:  {a)  TOTAL  BLOOD  FLOW  THROUGH 
SUBMAXILLARY  GLAND,  {b)  TOTAL  AMOUNT  OF  WATER 
TRANSFERRED  FROM  BLOOD  TO  GLAND.  (c)  TOTAL 
SECRETION  OF  SALIVA  (BARCROFT)        .  .  .  .52 

2.  COMPARISON  OF  CHANGES  IN  VOLUME  OF   SUBMAXILLARY 

GLAND  WITH  THE  OUTFLOW  OF  SALIVA  PRODUCED  BY 
STIMULATION  OF  THE  CHORDA  TYMPANI  NERVE 
(bunch) .52 

3.  TRACING   OF   VOLUME    OF   SUBMAXILLARY   GLAND,   SHOW- 

ING EFFECT  OF  STIMULATION  OF  THE  CHORDA  AFTER 
ADMINISTRATION    OF     10    MG.     ATROPINE     .  .  .53 

4.  TRACING   OF  VOLUME  OF  SUBMAXILLARY  GLAND  SHOWING 

DECREASE    ON    EXCITATION    OF    CHORDA      ...         54 

5.  TRACING    OF   VOLUME    OF    SUBMAXILLARY   GLAND,    SHOAV- 

ING  EFFECT  OF  CHORDA  STIMULATION  AFTER  OBSTRUC- 
TION  OF   THE   DUCT 55 

G.  DIAGRAM  SHOWING  THE  MANNER  IN  WHICH  THE  STOMACH 
IS  DIVIDED  INTO  TWO  CAVITIES,  SEPARATED  ONLY  BY 
A  DIAPHRAGM  OF  MUCOUS  MEMBRANE,  AND  STILL  IN 
MUSCULAR  AND  NERVOUS  CONTINUITY  .  .  .65 

7.  REPRODUCTION  OF  PLATE  FROM  RENE  DE  GRAAf'S 
TREATISE  "DE  SUCCO  PANCREATICO,"  REPRESENTING 
A     DOG     IN     WHICH     HE      HAD      ESTABLISHED      BOTH 

P.D.  h 


X  '  LIST    OF    ILLUSTRATIONS    AND    DIAGRAMS. 

FiarRE.  PAGE 

SALIVARY  AND  PANCREATIC  FISTULA,  SMALL  GLASS 
PHIALS  BEING  ATTACHED  TO  EACH  TO  COLLECT  THE 
SECRETIONS 81 

8.  EFFECT    OF    INJECTION   OF  ACID    INTO    LOOP    OF    SMALL 

INTESTINE  AFTER  DESTRUCTION  OF  ITS  NERVOUS 
CONNECTIONS 87 

9.  EFFECT    OF    SECRETIN    PREPARED    BY    THE     ACTION    OF 

DILUTE  ACID  ON  INTESTINAL  MUCOUS  MEMBRANE 
WHICH  HAD  BEEN  EXTRACTED  WITH  HOT  ABSOLUTE 
ALCOHOL 89 

10.  FORMATION  OF  ISLET  OF  LANGERHANS  FROM   SECRETORY 

ALVEOLI 100 

11.  EFFECT    OF    INJECTION    OF   SECRETIN  ON   THE   FLOW  OF 

PANCREATIC   JUICE   AND   OF   BILE         .  .  .  .117 

12.  DIAGRAM    (from    CANNON)    SHOWING    THE    APPEARANCE 

OF  A  LENGTH   OF   GUT   FILLED  WITH  FOOD  CONTENTS      140 

1 3.  RHYTHMIC   CONTRACTIONS   OF   THE  WALL   OF  THE   SMALL 

INTESTINE  (dog)  RECORDED  BY  INSERTING  A  RUBBER 
BALLOON  INTO  THE  LUMEN  OF  THE  GUT,  AND  CON- 
NECTING  IT   BY   A  TUBE   WITH   A  PISTON   RECORDER  .      141 


THE  PHYSIOLOGY  OF  DIGESTION. 


LECTUKE  I. 

THE    FOOD-STUFFS    AND    THEIR    CHANGES    DURING    DIGESTION 

THE"  MODE    OF    ACTION    OF    FERMENTS. 

Physiology  deals  with  the  sources  and  the  transformations 
of  energy  in  the  Uving  organism.  In  animals  the  whole  of 
the  energy  available  for  the  vital  processes  is  obtained  by  the 
combustion  of  the  food- stuffs,  i.e.,  the  union  of  their  carbon  and 
hydrogen  with  the  oxygen  taken  in  from  the  surrounding 
atmosphere.  The  office  of  digestion  being  to  prepare  the  food- 
stuffs for  absorption  into  the  fluids  of  the  body  and  for  utilisa- 
tion by  its  constituent  cells,  the  chapter  in  physiology  dealing 
w^ith  this  subject  logically  precedes  all  others.  In  the  following 
lectures  I  propose  to  deal  with  the  changes  undergone  by  the 
food  in  the  alimentary  canal,  and  especially  with  the  mechanisms 
by  which  these  changes  are  brought  about.  The  time  at  our 
command  will  not  allow  me  to  enter  into  full  details  in  every 
part  of  the  subject ;  I  shall  therefore  devote  my  chief  atten- 
tion to  those  questions  which  are  at  present  being  most  actively 
discussed  by  physiologists,  and  to  the  solution  of  which  I  am 
able  to  bring  the  experience  of  work  which  has  been  carried  out 
in  this  laboratory. 

In  the  bewildering  variety  of  foods  that  are  at  the  disposal 
of  civilised  man,  it  would  seem  at  first  sight.hopeless  to  attempt 

P.D.  R 


^  THE    PHYSIOLOGY    OF    DIGESTION. 

to  give  a  description  of  the  principles  which  underlie  the  diges- 
tion of  each  one  of  them.  A  chemical  examination  of  these 
food-stuffs,  however,  reveals  the  possibility  of  a  very  simj)le 
classification.  All  the  foods  which  serve  to  us  as  sources  of 
energy  are  themselves  derived  from  living  beings,  either  plant 
or  animal.  The  chemistry  of  the  food-stuffs  is,  therefore,  iden- 
tical with  the  chemistry  of  the  tissues  of  living  organisms.  The 
substances  which  are  utilised  in  the  building  up  of  a  plant  or 
animal  fall  into  one  of  three  main  groups,  which  are  also  the 
groups  into  which  our  food-stuffs  are  divided.  These  groups 
are — 

(1)  Proteids — nitrogenous  bodies  such  as  those  forming  the 
greater  part  of  meat  or  white  of  egg.  These  can  be  split  up 
readily  by  hydrolytic  agencies  into  a  whole  series  of  mono- 
amino-  and  diamino-  acids,  derived  chiefly  from  the  fatty  series 
but  partly  also  from  the  aromatic  series.  They  also  contain 
sulphur  as  an  integral  part  of  their  molecule,  chiefly  in  the 
form  of  cystin,  which  itself  is  derived  from  two  amino-acid 
groups. 

(2)  Carbohydrates,  including  the  starches  and  sugars. 

(3)  Fats,  which  are  compounds  of  glycerin  with  fatty  acids. 
I  have  spoken  of  these  foods  as  sources  of  energy  to  the  body. 

Is  this  their  sole  significance  ?  The  energy  value  of  food  is 
easily  determined  by  finding  how  much  energy  in  the  form  of 
heat  a  given  weight  of  it  will  evolve  when  burned  in  an  atmo- 
sphere of  oxygen.  In  this  way  we  might  find  the  following 
heat  equivalents  for  the  three  classes  of  food-stuffs,  namely — 

Proteids  ...         ...         ...     5'5  kilocalories. 

Carbohydrates  ...  ...     4'1  ,, 

Fats      9-5 

One  gramme  of  fats,  for  instance,  when  burned  in  an  atmo- 
sphere of  oxygen  to  CO2  and  H2O,  will  evolve  an  amount  of  heat 
which  is  sufficient  to  warm  9*5  kilogrammes  of  water  from  0°C. 


FOOD-STUFFS   AND    THEIR    CHANGES    DURING    DIGESTION.  O 

to  1°C.    If  the  energy  value  of  a  food -stuff  represents  its  whole 
value  to  the  organism,  we  should  expect  that  the  animal  would 
be  able  to  nourish  itself  and  discharge  its  normal  activities  at  the 
expense  of  any  one  of  these  food-stuffs,  provided  that  this  were 
given  in  proportion  to  its  energy  or  heat  value.     Within  limits 
this  is  the  case.     If  an  animal  be  made  to  do  more  work,  or  be 
exposed  to  external  cold,  so  that  it  needs  more  heat  to  main- 
tain its  normal  temperature,  the  amount  of  food  which  it  takes 
must  also  be  increased,  and  it  seems  to  be  a  matter  of  indiffer- 
ence to  the  organism  which  class  of  food-stuffs   is   used   to 
furnish  this  excess.     From  the  energy  point  of  view  the  value 
of  a  food  is  the  amount  of  heat  which  it  will  evolve  when 
burned  to  CO2  and  H2O.     From  this  point  of  view  the  nitrogen 
in  the  proteid  molecule  is  practically  valueless,  and  it  is  only 
the  C  and  H  atoms  in  the  proteid  which  can  be  regarded 
as  furnishing  energy  to   the  body.     If   an  animal  be  com- 
pelled to  satisfy  a  large  call  on  its  energies  by  taking  increased 
proteid  food,  the  useless  nitrogen  in  the  molecule,  which  is  set 
free  by  the  utilisation  and   combustion    of   the   carbon   and 
hydrogen,  must  be  discharged  from  the  body,  and  as  a  matter 
of  fact  we  find  that,  with  increased  proteid  diet,  there  is  corre- 
sponding increase  in  the  output  of  nitrogen  in  the  form  of  urea. 
As  a  source  of  energy,  proteid  cannot  be  regarded  as  presenting 
any    advantages    over    carbohydrate    and    fat.     In    fact,    it 
suffers  from  the  disadvantage  that,  for  tlie  utihsation  of  its 
energy,  nitrogen  has  to  be  split  off',  probably  in  the  form  of 
ammonia,  and  a  certain  amount  of  useless  work  has  to  be  done 
in  the  transformation  of  this  nitrogen  into  urea  and  its  excretion 
irom  the  body.     Although,  however,  the  nitrogen  in  the  food  is 
useless  as  a  source  of  energy,  its  presence  is  an  essential  con- 
dition for  the  utilisation  of  the  energy  of  the  other  food-stuffs, 
and  it  must  be  regarded,  therefore,  as  one  of  the  most  important 
-constituents  of  all  living  organisms.     In  fact,  the  protoplasm, 

b2 


4  THE    PHYSIOLOGY    OF    DIGESTION. 

the  active  part  of  the  organism,  consists  almost  entirely  of 
proteids  or  allied  bodies.  Fats  and  carbohydrates,  where 
they  occur  in  the  living  organism,  are  found  only  to  a  slight 
extent  in  combination  in  the  living  protoplasm  itself,  the  greater 
part  of  them  being  laid  down  as  store  material  for  the  future 
wants  of  the  active  growing  protoplasm.  Many  facts  show 
that  the  combustion  and  utilisation  of  the  energy  of  the  carbon 
and  hydrogen  of  the  food  take  place  in  the  protoplasm  itself, 
the  oxidisable  molecules  being  linked  on  to  the  central  living 
nucleus;  and  it  seems  that  nitrogen  plays  an  important  part 
both  in  this  linkage,  and  in  bestowing  on  the  complex  thus  pro- 
duced the  labiHty  or  instability  which  is  a  necessary  condition 
of  the  vital  processes  themselves. 

Essential  functions  of  all  living  beings  are  those  of  growth, 
repair,  and  in  the  higher  animals  death.  No  act  can  go  on 
without  involving  some  degree  of  disintegration  of  the  living 
nitrogenous  framework  of  the  tissue,  and  the  consequent  need 
of  repair.  In  every  living  cell,  therefore,  we  may  speak  of  tw^o 
kinds  of  chemical  changes,  or  of  tw^o  destinations  of  the  food- 
stuffs. In  the  first  place  there  are  the  changes  which  furnish 
the  energy  necessary  for  vital  manifestations,  movement, 
warmth,  etc.  As  sources  of  this  energy,  all  three  classes  of 
food-stuffs  can  be  employed,  their  value  being  given  by  their 
heat  equivalents  when  taken  as  food.  In  the  second  place  we 
have  the  changes  which  are  involved  in  the  disintegration, 
repair,  and  growth  of  the  living  protoplasm  itself.  In  this 
nutritional  metabolism  proteids  play  the  most  important  part, 
and  are  absolutely  essential  for  the  continuance  of  life.  An 
animal,  therefore,  can  theoretically  be  nourished  on  a  diet  of 
pure  proteid,  but  it  would  be  impossible  to  keep  an  animal  alive 
on  a  diet  consisting  either  of  pure  fat  or  of  pure  carbohydrate. 

These  three  classes  of  food-stuffs  being  essential  constituents 
of  all  our  foods,  the  use  of  the  processes  of  digestion  is  to 


FOOD-STUFFS    AND    THEIR    CHANGES    DURING    DIGESTION.  5 

render  them  tit  for  absorption  into  the  blood,  by  which 
they  may  be  carried  round  to  all  parts  of  the  body.  In 
most  cases  they  cannot  be  utilised  in  their  original  form 
by  the  living  cells.  It  must  be  remembered  that,  when  we 
nourish  ourselves  at  the  expense  of  an  animal  or  plant,  we 
are  taking  in,  not  only  the  current  coin  of  the  organism  which 
is  being  used  for  the  supply  of  energy  to  its  vital  processes, 
but  also,  and  to  a  much  larger  extent,  the  framework  forming 
the  machinery  of  the  organism,  as  well  as  its  stores  of  carbo- 
hydrate or  fat.  The  food-stuffs  therefore  as  we  ingest  them 
are  in  the  most  inactive  form  possible.  Practically  all  of 
them  are  colloidal,  free  from  taste  or  chemical  reaction,  and 
presenting  no  tendency  to  unite  with  oxygen,  or  indeed  to 
undergo  any  change  whatsoever,  apart  from  the  interference 
of  living  organisms  such  as  bacteria.  In  a  starving  animal, 
the  stores  of  carbohydrate  and  fat  and  the  proteid  structure 
of  the  living  cells  have  to  be  converted  into  a  soluble  form, 
transformed,  so  to  speak,  into  currency,  before  they  can  be 
utilised  by  other  living  cells  for  the  discharge  of  their  normal 
functions  and  the  maintenance  of  the  life  of  the  animal.  In 
the  same  way,  when  we  take  these  colloidal  or  insoluble 
stable  substances  into  our  alimentary  canal,  they  have  to 
be  dissolved  and  rendered  diffusible,  in  order  to  allow  of 
their  easy  transference  across  the  wall  of  the  gut  into  the 
blood  and  their  transport  to  the  tissue  cells.  On  fats  and 
carbohydrates,  therefore,  the  effect  of  digestion  will  be  to 
render  them  soluble  and  diffusible,  and  to  reduce  them  to  a 
condition  in  which  they  can  be  directly  assimilated  by  the 
cells  of  the  body.  The^e  latter  cannot  deal,  for  example,  with 
all  kinds  of  carbohydrate.  Many  an  animal  cell  will  starve 
when  presented  with  starch,  dextrin,  or  any  of  the  disac- 
charides,  such  as  maltose,  lactose,  or  cane  sugar.  It  is 
necessary,   therefore,    that   all    the    carbohydrates    shall   be 


6  THE    PHYSIOLOGY    OF    DIGESTION. 

reduced  in  the  alimentary  canal  or  in  its  walls  to  the  form 
of  monosaccharides.  As  regards  proteids,  the  processes  of 
digestion  have  a  different  significance  according  as  we  are 
dealing  with  their  value  as  givers  of  energy  or  their  value  as 
builders  up  of  the  living  protoplasm.  If  the  proteids  of  the 
food  are  to  be  oxidised  and  utilised  as  a  source  of  energy,  it  is 
only  necessary  to  render  them  soluble  so  as  to  assist  their 
absorption.  If,  however,  they  are  to  be  built  up  as  integral 
parts  of  the  living  cells,  to  take  the  place  of  molecules  which 
have  been  destroyed  in  the  wear  and  tear  of  the  processes 
of  life,  a  much  more  profound  change  is  necessary.  The 
proteids  of  the  cells  from  different  parts  of  the  body  have 
different  molecular  constitutions.  Not  only  do  they  differ 
among  themselves,  but  they  differ  very  largely  from  many 
of  the  proteids  which  may  be  taken  in  with  the  food.  A 
child  is  able  to  obtain  material  for  the  growth  of  his  brain 
cells,  his  muscle  cells,  his  liver  cells,  from  a  diet  containing 
proteid  in  the  form  of  caseinogen,  of  vegetable  gluten,  of  meat 
fibrin,  or  vegetable  proteid,  such  as  edestin.  A  reference  to 
the  following  tables  will  show  the  striking  difference  in  com- 
position between  the  various  proteids  of  the  food  and  the 
proteids  which  have  to  be  formed  from  them  in  the  living 
tissues. 

We  may  take  for  example  the  manner  in  which  the  nitrogen 
is  combined  in  the  different  proteids.  For  purposes  of  classi- 
fication the  nitrogen  can  be  divided  into  three  fractions,  accord- 
ing to  its  behaviour  in  the  product  of  the  acid  hj^drolysis  of  the 
proteid.     These  fractions  are — 

(a)  The  portion  which  is  driven  off  as  ammonia  by 
heating  the  acid  mixture  with  alkalies  or  magnesia, 
the  so-called  ammonia-  or  amide-nitrogen ; 

{b)  That  contained  in  the  form  of  monoamino-acids ; 

(c)  That  contained  as  diamino-acids,  or  as  bases  such  as 


FOOD-STUFFS    AND    THEIR    CHANGES    DURING    DIGESTION.  7 

guanidine,    histidine,  or   arginine,    etc.,  known    as 

basic    nitrogen    and    precipitated   on    addition    of 

phosphotungstic  acid. 

In  the  following  table*  is  given  the  relative  distribution  of 

the  nitrogen  in  various  proteids  among  these  three  groups  : — 


Proteid. 

Amide  N. 

Basic  N. 

Monamino-N. 

Crystallised  serum  albumin  .  . 

6-5 

34-4 

60-2 

Crystallised  egg  albumin 

8-5 

21-3 

67-8 

Crystallised  edestin    .  . 

10-2 

38-1 

55-0 

Caseinogen  of  milk    .  . 

10-4 

28-9 

62-0 

Serum  globulin 

8-9 

25-0 

68-8 

Still  greater  differences  are  noticeable  when  we  examine  the 
content  in  certain  individual  constituents  of  the  proteid 
molecule,  thus : — 


Proteid. 

Arginiu. 

Lysin. 

Histidin. 

Tyrosii). 

Cy  still. 

Edestin 

14-07 

— 

— 

— 

— 

Caseinogen 

4-84 

5-80 

2-59 

4-5 

— 

Blood  fibrin 

— 

— 

— 

3-82 

1-17 

Gluten  fibrin  (wheat) 

3-05 

— 

1-53 

— 

— 

Zein  (maize) 

1-82 

— 

0-81 

— 

— 

Egg  albumin 

— 

— 

— 

1-5 

0-29 

Serum  albumin    .  . 

— 

— 

— 

20 

2-15 

It  is  evident  that  to  form  serum  albumin,  for  instance,  out 
of  w^heat  gluten,  an  entire  reconstruction  is  necessary.  This 
can  only  be  accomplished  by  taking  the  proteid  molecule  to 


From  Hofmeister,  "  Ergebnisse  der  Physiologic,"  I.,  i.  (1902),  p.  777. 


8  THE    PHYSIOLOGY    OF    DIGESTION. 

bits,  and  by  selecting  certain  of  its  constituent  parts  and 
building  these  up  in  the  proper  proportions  to  form  a  new 
proteid  molecule.  For  the  purposes  of  nutrition  the  changes 
in  the  proteid  molecule  in  the  intestine  must  be  profound,  and 
the  extent  of  the  change  must  be  greater  the  more  variation 
there  is  in  the  composition  of  the  proteid  of  the  food  from 
the  composition  of  the  proteids  of  the  tissues. 

In  primitive  alimentary  canals,  every  cell  lining  the  canal 
may  be  endowed  with  amoeboid  properties  and  capable  of 
devouring  food  particles,  the  subsequent  changes  in  the  food 
particles  to  fit  them  for  their  journey  through  the  rest  of  the 
body  being  performed  in  the  body  of  the  cell  itself.  In  all 
the  higher  animals,  however,  including  ourselves,  the  greater 
part  of  the  preparation  of  the  food  is  accomplished  extra- 
cellular ly  in  the  lumen  of  the  alimentary  canal,  and  the 
changes  are  effected  by  means  of  special  digestive  juices, 
which  are  formed  by  the  activity  of  masses  of  cells  produced 
as  outgrowths  from  the  wall  of  the  canal.  The  digestive 
juices  attack  the  food-stuffs  by  means  of  ferments,  and  in 
every  case  the  action  of  these  ferments  is  hydrolytic,  the  food- 
stuffs taking  up  one  or  more  molecules  of  water  and  under- 
going dissociation  into  simpler  molecules.  Since  each  class  of 
food-stuff  requires  a  different  ferment,  a  great  variety  of 
ferments  are  concerned  in  the  processes  of  digestion.  In  the 
following  list  the  ferments  of  the  alimentary  canal  are  enume- 
rated, together  with  the  substances  on  which  they  act  and 
their  ultimate  products  : — 


Food-stuff. 

Ferment. 

Product  of  action. 

Proteids  (all) 

Pepsin 

Albumoses  and  peptones 
(aniino-acids  after  pro- 
longed action). 

Trypsin 

Peptones,  amino  -  acids 
and  bases  (complete 
hydrolysis). 

FOOD-STUFFS    AND    THEIR    CHANGES    DURING    DIGESTION. 


9 


Food-stuff. 

Hydrated  proteids  and 

certain    coagulable 

proteids    such   as 

fibrin  and  caseinogen 

Carbohydrates — ■ 
Starch 


Maltose 
Cane  sugar 
Milk  sugar 


Ferment. 
E  rep  sin 


Product  of  action. 
Amino-acids,  etc. 


Amylase  of  saliva  .  . 
,,         of  pancrea- 
tic juice 
Maltase 
Invertase 
Lactase 


Fats 


Dextrin  and  maltose. 

Glucose. 

Glucose  and  fructose. 

Glucose  and  galactose. 

Fatty  acids  and  glycerin. 


Lipase  (steapsin) 

It  will  be  seen  that,  as  the  end  result  of  digestion,  the 
enormous  variety  of  food  taken  by  man  is  reduced  into  a 
fairly  small  number  of  simpler  bodies.  These  end  products 
are  : — 

(1)  Carbohydrates. 

The   monosaccharides :    glucose,   fructose  or  Inevulose, 
and  galactose. 

(2)  Fats :  fatty  acids,  or  (in  alkaline  medium)  soaps,  and 
glycerin. 

(3)  Proteids.  Here  we  have  a  great  variety  of  mono-  and 
diamino-  acids,  which  may  be  enumerated  as  follows  : — 

MONOAMINO-ACIDS  — 

Glycine  (aminoacetic  acid) 

Alanine  (aminopropionic  acid)  .  . 

Serine  or  oxyalanine  (oxyaminopropionic  acid)  I   Monobasic  acids 


Aminovalerianic  acid 

Leucine  (aminoisobutylacetic  acid) 

Isoleucine  (aniinocaproic  acid)  .  . 

Aspartic  acid 

Glutamic  acid 

Phenylalanine 

Tyrosine  (oxyphenylalanine) 

Proline  (pyrrolidine  carboxylic  acid)    .  . 

Oxyproline  (oxypyrrolidine  carboxylic  acid) 

Tryptophane  (indol- aminopropionic  acid) 


of  fatty  series. 


Dibasic  acids. 

Benzene   (aromatic) 
derivatives. 

Heterocyclic 

compounds. 


10  THE    PHYSIOLOGY    OF    DIGESTION. 


■  ■  ]  The 


DiAMINO-ACIDS    AND    THEIR    COMPOUNDS 

Lysine  (diaminocaproic  acid) 

Arginiiie  (guaiiidinaininovalerianic  acid)         ... 

TT-  J.-J-       /  ■     -J-       J     •     ±-     \  \       '  hexone  bases. 

Histidme  (a  pyrimidine  derivative)  .  .  / 

Diaminotrioxydodecoic  acid  .  .  derived  from  a  12  carbon  acid. 

Cystin  (derived  from  aminothiolactic  acid)         ■  •  i.  j 

The  whole  of  these  digestive  changes  in  the  food-stuffs  are 
to  be  ascribed  to  the  action  of  ferments.  When,  following  the 
food  through  the  walls  of  the  intestine,  we  have  to  deal  with 
the  processes  by  which  it  is  assimilated  into  the  living  cell, 
and  the  processes  by  which  it  undergoes  oxidation  or  disinte- 
gration and  so  furnishes  energy  to  the  body,  as  well  as  the 
processes  by  which  one  cell  may  be  nourished  at  the  expense 
of  other  less  important  cells,  in  every  case  we  find  that  ferments 
are  involved.  It  is  impossible,  therefore,  to  proceed  further 
with  our  study  of  the  digestive  juices,  without  trying  to  form 
some  conception  of  the  manner  in  which  these  bodies,  the 
most  important  factors  in  the  maintenance  of  life,  effect  their 
changes. 

It  is  important  to  note  that  all  the  changes  wrought  by 
the  digestive  ferments  on  the  food- stuffs  are  hydrolytic  in 
character.  Thus  the  proteids  are  transformed  by  the  action 
of  pepsin  or  trypsin  into  the  hydrated  proteids,  albumoses  or 
peptones,  and  these  again  by  the  further  process  of  hydration 
into  the  amino-acids.  Starches  take  up  water  with  the 
formatioli  of  maltose.  Each  molecule  of  the  disaccharides 
takes  up  one  molecule  of  water,  and  is  converted  into  two 
molecules  of  a  monosaccharide.  Each  molecule  of  neutral 
fat  takes  up  three  molecules  of  water  to  be  transformed  into 
glycerin  and  the  corresponding  fatty  acid.  If  the  food-stuffs 
are  placed  in  contact  with  water,  either  at  ordinary  tempera- 
tures or  at  the  temperature  of  the  body,  and  bacteria  be 
excluded   from   the    solution,    they    undergo    practically    no 


THE    MODE    OF    ACTION    OF    FERMENTS.  11 

change.  If  the  sokition  be  warmed,  a  slow  process  of  hydra- 
tion takes  place,  which  is  quickened  by  rise  of  tempera- 
ture, so  that  in  water  heated  above  boiHng  point  hydration 
occurs  with  considerable  rapidit3\  We  may  say,  then,  that 
the  action  of  the  ferments  is  to  quicken  a  process  of  hydro- 
lysis which,  without  their  presence,  would  take  an  infinity 
of  time  for  its  accomplishment.  In  this  respect  their  action 
is  similar  to  that  of  acids,  and  indeed  of  a  whole  class  of 
bodies  which  are  spoken  of  as  eatalysers  or  catalysts.  A 
catalyser  is  a  substance  which  will  increase  the  velocity  of 
a  reaction  without  adding  in  any  way  to  the  energy  changes 
involved  in  the  reaction,  or  taking  any  part  in  the  formation 
of  the  end  products.  Since  the  catalyser  is  unchanged  in 
the  chemical  process  which  it  brings  about  or  hastens,  a  very 
small  quantity  is  able  to  influence  reactions  involving  large 
quantities  of  other  substances.  By  adding  acids  to  a  watery 
solution  of  the  food-stuffs,  the  process  of  hydrol^^sis  is 
quickened  in  proportion  to  the  strength  and  concentration 
of  the  acid.  The  effective  catalytic  agents  in  this  process 
appear  to  be  the  hydrogenions  of  the  free  acid.  There  are 
many  other  substances  besides  the  free  acids,  which  may  act 
as  eatalysers,  and  a  study  of  the  conditions  under  which 
catalysis  takes  place  may  throw  some  light  on  the  essential 
nature  of  the  action  of  ferments. 

The  velocity  of  almost  any  reaction  in  chemistry  can  be 
altered  by  the  addition  of  some  or  other  catalytic  agent,  and 
there  are  few  of  the  ordinary  reactions  in  which  catalysis  does 
not  play  some  part.  Among  such  processes  we  may  instance 
the  action  of  spongy  platinum  on  hydrogen  peroxide.  Hydro- 
gen peroxide  undergoes  slow  spontaneous  decomposition  into 
water  and  oxygen.  If,  however,  a  little  spongy  platinum  be 
added  to  it,  it  is  at  once  seen  to  decompose  rapidly  with  the 
evolution  of  bubbles  of  oxygen,  and  the  action  does  not  cease 


12  THE    PHYSIOLOGY    OF    DIGESTION. 

until  the  whole  of  the  hydrogen  peroxide  has  been  destroyed. 
Spongy  platinum  is  able  in  the  same  way  to  quicken  a  very 
large  number  of  chemical  reactions.  Thus  sulphur  dioxide 
and  oxygen  when  heated  together  will  combine  very  slowly ; 
the  combination  becomes  rapid  if  a  mixture  of  the  two 
gases  be  passed  over  heated  platinum.  The  same  reaction, 
namely  the  combination  of  sulphur  dioxide  with  oxygen,  may 
be  quickened  by  the  addition  of  a  small  trace  of  nitric  oxide, 
and  this  fact  is  made  use  of  in  the  manufacture  of  sulphuric 
acid  on  a  commercial  scale  by  the  oi'dinary  lead  chamber 
process.  Hydrogen  peroxide  and  hydriodic  acid  slowly  inter- 
act with  the  formation  of  water  and  iodine.  This  reaction 
may  be  quickened  by  the  addition  of  many  substances,  among 
which  w^e  may  mention  molybdic  acid. 

It  might  be  thought,  however,  that,  although  there  is  this 
superficial  resemblance  between  the  action  of  catalysers  and 
that  of  ferments,  certain  important  characteristics  of  the 
ferments  might  serve  to  make  a  wide  cleavage  between  the 
two  processes.  Thus  among  the  ferments  we  find  a  marked 
specificity.  We  may  take  as  examples  the  ferments  which 
act  on  the  disaccharides.  Any  of  the  disaccharides,  whether 
natural  or  artificial,  can  be  readily  converted  by  treatment 
with  acids  into  the  corresponding  monosaccharides.  Thus 
cane  sugar  treated  in  this  way  gives  equal  parts  of  fructose 
and  glucose.  Lactose  will  give  equal  parts  of  glucose  and 
galactose.  Maltose  is  entirely  transformed  into  glucose. 
When  we  come  to  the  ferments,  however,  we  find  that  inver- 
tase,  which  quickly  transforms  cane  sugar  into  fructose  and 
glucose,  has  not  the  slightest  action  on  either  of  the  other 
disaccharides.  In  order  to  spUt  up  lactose  we  have  to  make 
use  of  a  special  ferment,  lactase  ;  and  similarly  for  the  con- 
version of  maltose  into  glucose  we  must  employ  the  ferment 
maltase.     The  action  of  these  ferments  is  not,  however,  so 


THE    I\I01)K    OF    ACTION    OF    FERMENTS.  Vd 

specific  as  would  appear  when  we  confine  our  attention  to  the 
food-stuffs  themselves.  Thus  invertase  not  only  breaks  up  cane 
sugar,  but  also  causes  hydrolysis  of  rafifinose  and  gentianose. 
Lactase,  in  addition  to  its  action  on  lactose,  or  milk-sugar,  has 
the  property  of  hydrolysing  all  the  /8-galactosides.  Emulsin 
liydrolyses  the  yS-giucosides  {i.e.,  most  of  the  natural  glucosides),. 
as  well  as  the  /8-galactosides,  including  milk-sugar.  Maltase 
not  only  converts  maltose  into  glucose,  but  also  liydrolyses 
all  the  a-glucosides.  On  the  other  hand,  although  some  sub- 
stances such  as  platinum,  especially  in  the  finely  divided 
form  of  platinum  black,  can  influence  a  very  large  number  of 
reactions,  they  cannot  influence  all  chemical  reactions.  Potas- 
sium bichromate  will  act  as  the  catalyser  for  the  oxidation 
of  hydriodic  acid  by  bromic  acid,  but  not  for  the  oxidation  of 
the  same  substance  by  iodic  acid.  Iron  and  copper  salts  in 
minute  traces  will  quicken  the  oxidation  of  potassium  iodide 
by  potassium  persulphate, but  have  no  influence  on  the  course 
of  the  oxidation  of  sulphur  dioxide  by  potassium  persulphate. 
Tungstic  acid  increases  the  velocity  of  oxidation  of  hydriodic 
acid  by  hydrogen  peroxide,  but  has  no  effect  on  the  velocity 
of  oxidation  of  hydriodic  acid  by  bromic  acid,  and  these 
examples  may  be  multiplied  to  any  extent.  One  cannot 
therefore  regard  the  limitation  of  action  of  the  ferments  as 
justifying  any  fundamental  distinction  being  drawn  between 
the  action  of  this  class  of  substances  and  that  of  catalysts. 

Another  contrast  has  been  drawn  between  the  effects  of  rise 
of  temperature  on  these  two  classes  of  phenomena.  Whereas 
the  influence  of  most  catalysers  on  the  velocity  of  a  reaction 
increases  rapidly  with  increase  of  temperature,  in  the  case  of 
ferments  this  increase  occurs  only  up  to  a  certain  point. 
This  point  is  spoken  of  as  the  optimum  temperature  of  the 
ferment  action.  If  the  mixture  be  heated  above  this  point  the 
action  of  the  ferment  rapidly  slows  off  and  then  ceases.     This 


14  THE    PHYSIOLOGY    OF    DIGESTION. 

contrast  again  is  only  apparent.  The  ferments  are  unstable 
bodies  easily  altered  by  change  in  their  physical  conditions, 
and  destroyed  in  all  cases  at  a  temperature  consider- 
ably below  that  of  boiling  water.  We  may  say,  therefore, 
that  ferment  actions,  like  catalytic  actions,  are  quickened  by 
rise  of  temperature,  but  this  effect  of  temperature  is  finally 
put  a  stop  to  by  the  destruction  of  the  ferment.  The  same 
effect  of  temperature  is  observed  in  the  case  of  inorganic 
catalysers  whose  physical  state  is  susceptible,  like  that  of  the 
ferments,  to  the  action  of  heat.  By  the  passage  of  electric 
sparks  between  two  platinum  terminals  immersed  in  distilled 
water,  minute  ultra-microscopic  particles  of  platinum  are 
thrown  off  into  the  fluid,  so  that  a  colloidal  solution  of  platinum 
is  obtained.  This  colloidal  platinum  exerts  marked  catalytic 
effects  on  various  reactions,  e.g.,  on  the  decomposition  of 
hydrogen  peroxide  and  on  the  combination  of  hydrogen  and 
oxygen.  The  effect,  however,  presents  an  optimum  tempera- 
ture, owing  to  the  fact  that  the  colloidal  platinum  is  altered, 
coagulated,  and  thrown  out  of  solution  when  this  is  heated  to 
near  boiling  point.  We  may  therefore  employ  either  class  of 
reactions  in  trying  to  form  some  conception  of  the  processes 
which  are  actually  involved. 

Very  many  theories  have  been  put  forward  to  account  for 
this  action  of  catalysers  or  of  ferments.  Many  of  them 
are  merely  transcriptions  in  words  of  the  processes  which 
actually  occur,  and  fail  to  throw  any  light  on  their  real 
nature.  The  essential  phenomena  involved  fall  directly  into 
two  classes.  In  the  first  place,  it  must  be  remembered  that 
the  molecules  of  any  liquid  or  gas,  which  are  situated  in  the 
surface  layer  in  contact  with  some  other  substance,  are  in  a 
different  condition  from  those  in  the  interior  of  the  fluid.  In 
gases  this  difference  results  in  a  diminution  of  the  pressure 
or  of  the  translatory  velocity  of  the  molecules  in  the  surface^ 


THE    MODE    OF    ACTION    OF    FERMENTS.  15 

and  therefore  to  a  condensation  of  the  gas  here.  After  a  glass 
vessel  has  been  evacuated  by  means  of  a  mercury  pump,  it  is 
found  that  the  vacuum  slowly  diminishes,  owing  to  the  gradual 
giving  off  by  the  glass  of  the  so-called  occluded  gas,  i.e.,  gas 
which  has  been  adherent  to  its  surface,  and  perhaps  in  actual 
solution  in  its  superficial  layers.  The  glass  gives  up  this 
occluded  gas  very  slowly,  and  in  order  to  make  a  perfect 
vacuum  the  process  of  evacuation  has  to  be  repeated  several 
times,  and  the  glass  must  be  heated  considerably  during  the 
operation.  In  many  cases  the  combination  of  gases  can  be 
hastened  by  increasing  the  surface  to  which  they  are  exposed, 
as  by  passing  them  over  broken  porcelain  or  powdered  charcoal. 
The  power  of  a  solid  to  condense  gases  on  its  surface  varies  with 
the  nature  of  the  solid  and  the  nature  of  the  gas.  It  is  very 
marked  in  animal  charcoal,  especially  in  the  case  of  gases  such 
as  ammonia  or  sulphur  dioxide.  Metals  also  have  some  power 
of  occluding  or  condensing  at  their  surfaces.  Thus  both 
platinum  and  palladium  will  absorb  a  very  large  amount 
of  hydrogen.  In  the  same  way  silver  has  the  power  of  occlud- 
ing oxygen.  That  this  effect  is  a  surface  phenomenon  is 
shown  by  the  fact  that  the  power  of  these  metals  or  sub- 
stances to  occlude  gases  is  in  proportion  to  their  state  of 
subdivision.  The  same  proportionality  holds  between  the 
surface  of  these  substances  and  their  catalytic  power.  Thus 
the  efficacy  of  platinum  in  hastening  the  combination  of 
hydrogen  and  oxygen  is  in  direct  proportion  to  its  fineness 
of  subdivision,  and  is  best  marked  when  the  metal  is  reduced 
to  ultra-microscopic  dimensions,  as  in  the  colloidal  solution 
of  platinum.  Every  colloidal  solution  must  be  regarded  as 
presenting  an  enormous  surface  in  proportion  to  the  mass  of 
substance  in  solution.  Thus  a  sphere  of  10  cubic  centi- 
metres with  a  surface  of  22  square  centimetres,  if  reduced 
to  a  fine  powder  consisting  of  spherules  about  0*00000025  cm. 


16  THE    PHYSIOLOGY    OF    DIGESTION. 

in  diameter,  will  have  a  surface  of  20,000,000  square  centi- 
metres, i.e.,  nearly  half  an  acre.* 

There  is  a  direct  proportionality,  therefore,  between  the 
l)Ower  of  a  substance  to  condense  a  gas  on  its  surface  and  its 
power  to  quicken  the  velocity  of  chemical  changes  in  which 
the  gas  is  involved.  The  same  process  of  condensation  occurs 
with  dissolved  substances.  Just  as  the  pressure  of  a  gas  in 
immediate  contact  with  a  solid  body  is  diminished,  so  the 
osmotic  pressure  of  a  substance  in  solution  is  diminished 
at  the  surface.  Hence  there  is  a  diffusion  of  dissolved 
substances  tow^ards  the  region  of  lower  osmotic  pressure 
i.e.,  a  concentration  of  dissolved  substances  at  the  surface  of 
contact.  It  was  suggested  by  Faraday  that  the  catalytic  pro- 
perty of  surfaces  was  due  to  this  condensation  of  molecules, 
and  the  consequent  bringing  of  the  two  sets  of  molecules 
within  each  other's  sphere  of  influence.  Whether  this  is  the 
sole  factor  involved  is  doubtful,  since  mere  compression  of 
gases  or  increased  concentration  of  solutions  does  not  in  the 
majority  of  cases  result  in  such  a  quickening  of  the  velocity  of 
reaction  as  is  brought  about  by  the  effect  of  the  surface. 

It  is  possible  that  this  condensation  effect  may  in  every 
case  be  combined  with  the  second  factor,  which  we  must  now 
consider,  namely,  the  formation  of  intermediate  products.  If 
we  take  an  alkaline  solution  of  indigo,  and  boil  it  with  some 
glucose,  the  indigo  is  reduced,  giving  up  its  oxygen  to  the 
glucose.  The  mixture  therefore  becomes  colourless.  On 
shaking  with  air,  the  colourless  reduction  product  of  the 
indigo  absorbs  oxygen  from  the  atmosj)here  and  is  re-trans- 
formed into  indigo.  These  two  processes  can  be  repeated 
until  the  whole  of  the  glucose  is  oxidised,  and  the  process  can 
be  made  continuous  if  air  or  oxygen  be  bubbled  through  a  hot 

*  V.  Mellor's,  "Chemical  Statics  and  Dynamics"  (Longman's,  1904),  esp.    pp.  245 
ct  HPq. 


THE    MODE    OF    ACTION    OF    FERMENTS.  17 

alkaline  solution  of  glucose  containing  a  small  trace  of  indigo. 
In  this  case  the  indigo  does  not  add  to  the  energy  of  the 
reaction.  It  appears  unchanged  among  the  final  products, 
and  a  small  amount  may  he  used  to  effect  the  change  of  an 
infinite  quantity  of  glucose.  It  therefore  may  be  said  to  act 
as  a  ferment  or  catalytic  agent.  Instead  of  an  alkaline 
solution  of  indigo,  we  may  use  an  ammoniacal  solution  of 
cupric  oxide  for  the  purpose  of  carrying  oxygen  from  the 
atmosphere  to  the  glucose.  This  is  reduced  to  cuprous 
hydrate  on  heating  with  sugar,  but  cupric  hydrate  can  be  at 
once  re-formed  by  shaking  up  the  cuprous  solution  with  air. 
It  has  been  thought  that  a  large  number  or  all  of  the  catalytic 
reactions  occur  in  the  same  way  by  two  stages,  i.e.,  by  the 
formation  of  an  intermediate  product.  Thus  in  the  ordinary 
process  for  the  manufacture  of  sulphuric  acid  the  nitric  oxide 
may  be  supposed  to  combine  with  the  oxygen  of  the  air  to 
form  nitrogen  peroxide.  This  interacts  with  sulphur  dioxide, 
giving  sulphur  tiioxide  and  nitric  oxide  once  more.  The 
nitric  oxide,  which  we  alluded  to  before  as  the  catalyser,  may 
in  this  way  be  regarded  as  the  carrier  of  oxygen  from  air  to 
sulphur  dioxide.  It  has  been  suggested  that  the  action  of 
spongy  platinum  or  colloidal  platinum  rests  on  the  same  pro- 
cess, and  that  in  the  oxidation  of  hydrogen,  for  instance,  PtO 
or  Pt02  is  formed  and  at  once  reduced  by  the  hydrogen  with 
the  formation  of  water. 

There  is  a  certain  amount  of  experimental  evidence  in  favour  of  this 
hypothesis.  According  to  Engler  and  Wohler,"^  platinum  black,  which 
has  been  exposed  to  oxygen,  in  virtue  of  the  gas  which  it  has  occluded, 
has  the  power  of  turning  potassium  iodide  and  starch  blue.  This  power 
is  not  destroyed  by  heating  to  260^  in  an  atmosphere  of  CO.j,  or  bj'  wash- 
mg  with  hot  water.  On  exposure  of  the  platinum  black  to  hydrochloric 
acid,  a  certain  amount  is  dissolved,  and  the  substance  loses  its  effect  on 
potassium  iodide.     The  amount  dissolved  corresponds  with  the  amount 

^  Quoted  by  Mellor,  loc.  cit.,  p.  269. 
P.D.  C 


18  THE    PHYSIOLOGY    OF    DIGESTION. 

of  iodine  liberated  from  potassiuixi  iodide,  and  also  with  the  amount 
of  oxygen  occluded,  the  (soluble)  platinum  and  oxygen  being  in  the 
proportions  necessary  to  form  the  compound  PtO. 

But  why  should  a  reaction  take  place  more  quickly  if  it 
occurs  in  two  stages  instead  of  one  ?  The  formation  of  an 
intermediate  compound  can  only  be  regarded,  as  Ostwald  has 
pointed  out,  as  a  sufficient  explanation  of  a  catalytic  process, 
when  it  can  be  demonstrated  by  actual  experiment  that  the 
rapidity  of  formation  of  the  intermediate  compound  and  the 
rapidity  of  its  decomposition  into  the  end-products  of  the 
reaction  are  in  sum  greater  than  the  velocity  of  the  reaction 
without  the  formation  of  the  intermediate  body.  In  the  case 
of  one  reaction  this  requirement  has  been  fulfilled.  The 
catalytic  action  of  molybdic  acid  on  the  interaction  of  hydriodic 
acid  and  hydrogen  peroxide  has  been  explained  by  assuming 
that  the  first  action  which  takes  place  is  the  formation  of 
permolybdic  acid,  which  then  interacts  with  the  hydrogen 
iodide  to  form  water  and  iodine.  Now  it  has  been  actually 
shown — (1)  that  permolybdic  acid  is  formed  by  the  action  of 
hydrogen  peroxide  on  molybdic  acid  ;  (2)  that  permolybdic 
acid  with  hydriodic  acid  produces  water  and  iodine ;  (3)  that 
the  velocity  with  which  these  two  reactions  occur  is  much 
greater  than  the  velocity  of  the  interaction  of  hydrogen 
peroxide  and  hydriodic  acid  by  themselves. 

Although  we  may  find  it  difficult  to  explain  why  a  reaction 
should  occur  more  quickly  in  the  presence  of  a  catalyser  by  the 
formation  of  these  intermediate  bodies,  certain  simple  analogies 
may  help  us  to  comprehend  how  a  factor  which  introduces 
no  energy  can  yet  assist  the  process.  Thus  a  man  might 
stand  to  all  eternity  before  a  perpendicular  wall  twenty  feet 
high.  Since  he  cannot  reach  its  top  at  one  jump,  he  is  unable 
to  get  there  at  all.  The  introduction  of  a  ladder  will  not  in  any 
way  alter  the  total  energy  he  must  expend  on  raising  his  body 


THE    MODE    OF    ACTION    OF    FERMENTS.  19 

for  twenty  feet,  but  will  enable  him  to  attain  the  top.  Or 
we  might  imagine  a  stone  perched  at  the  top  of  a  high  hill. 
The  passive  resistance  of  the  system,  the  friction  of  the  stone 
and  its  inertia,  will  tend  to  keep  it  at  rest,  even  though  it  be 
on  a  sloping  surface  and,  therefore,  tending  to  slide  or  roll  to 
the  bottom.  If,  however,  it  be  rolled  to  the  edge,  to  a  point 
where  there  is  a  sudden  increase  in  the  rapidity  of  slope,  it 
may  roll  over,  and,  having  once  started  its  downward  course, 
its  momentum  will  carry  it  to  the  bottom.  The  amount  of 
energy  set  free  by  the  stone  in  its  fall  will  not  vary  whether 
the  course  be  a  uniform  one,  or  whether  it  falls  over  a  preci- 
pice at  one  time  and  rolls  down  a  gentle  slope  at  another.  It 
is  evident  that,  by  a  mere  alteration  of  the  slope  or,  in  the 
case  of  a  chemical  reaction,  of  the  velocity  of  part  of  its  course, 
a  change  in  the  system  may  be  initiated  and  brought  to  a 
conclusion  which,  without  this  alteration,  would  never  take 
place.  We  have,  therefore,  to  inquire  in  the  case  of  enzymes 
or  ferments  how  far  their  action  is  to  be  explained  by  surface 
l^henomena,  or  by  the  formation  of  intermediate  compounds 
between  the  ferment  and  the  substance  it  acts  upon  (w^hich  is 
generally  known  as  the  substrate).  This  discussion  we  may 
defer  until  the  next  lecture. 


c2 


LECTUEE   II. 

THE    MODE    OF    ACTION    OF    FERMENTS    (continued). 

We  have  seen  that  catalytic  phenomena  may  be  explamed^ 
m  part  at  any  rate,  by  the  formation  of  an  intermediate  com- 
pound between  the  catalyst  and  the  substance  or  substances 
which  are  undergoing  change  (the  substrate) ;  and  the  question 
arises  whether  the  action  of  ferments  may  not  be  accompanied 
by  the  formation  of  some  such  intermediate  compound. 
Since  the  action  of  ferments,  like  that  of  catalysts,  consists 
essentially  in  the  quickening  up  of  processes  which  would 
otherwise  occur  at  an  infinitely  slow  velocity,  we  must  first 
inquire  whether  the  study  of  the  velocity  of  the  reaction  will 
throw  any  light  upon  the  number  of  substances  taking  part 
in  the  reaction,  and,  therefore,  upon  the  question  whether  the 
ferment  is  itself  involved  at  some  stage  of  the  reaction.  It  is, 
well  known  that  the  velocity  of  a  reaction  does  depend  on  the 
number  of  substances  involved.  As  an  illustration,  we  may 
take  first  the  case  of  a  reaction  involving  a  change  in  one 
substance.  If  arseniuretted  hydrogen  be  heated,  it  undergoes 
decomposition  into  hydrogen  and  arsenic.  This  decomposition 
is  not  immediate,  but  takes  a  certain  time,  and  the  velocity 
with  which  the  change  occurs  depends  on  the  temperature.. 
At  any  given  temperature  the  amount  of  substance  changed 
in  the  unit  of  time  varies  with  the  concentration  of  the 
substance.  If,  for  instance,  one-tenth  of  the  gas  be  dis- 
sociated in  the  first  minute,  in  the  second  minute  a  further 
tenth  of  the  gas  will  also  be  dissociated.     Thus,  if  we  start 


THE    MODE    OF    ACTION    OF    FERMENTS.  21 

"with  1,000  grammes  of  substance,  at  the  end  of  the  first 
minute  100  grammes  will  have  been  dissociated,  and  900  of 
the  original  substance  will  be  left.  In  the  second  minute 
one-tenth  again  of  the  remaining  substance  will  be  dissociated, 
i.e.,  90  grammes,  leaving  810  grammes.  In  the  third  minute 
81  grammes  will  be  dissociated,  leaving  729  grammes.  We 
see,  therefore,  that  the  amount  changed  in  the  unit  of  time 
will  always  bear  the  same  ratio  to  the  whole  substance  which 
is  to  be  changed,  and  will,  therefore,  be  a  function  of  the 
concentration  of  this  substance.  Put  in  the  form  of  an 
equation,  we  may  say  that  </>,  the  amount  changed  in  the  unit 
of  time,  will  be  equal  to  KC,  where  K  is  a  constant,  varying 
with  the  substance  in  question  and  with  the  temperature, 
and  C  represents  the  concentration  of  the  substance.  The 
equation  <^  =  KC  applies  to  a  unimolecular  reaction. 

If,  however,  two  substances  are  involved,  the  equation  will 
be  rather  different.  In  this  case  the  amount  of  change  in 
a  unit  of  time  will  be  a  function  of  the  concentration  of 
each  of  the  substances,  and  the  form   of  the  equation  will  be 

c^  -  K  (C,  X  C,). 
In  the  case  of  the  unimolecular  reaction,  halving  the  concen- 
tration of  the  substance  will  halve  the  amount  of  substance 
changed  in  the  unit  of  time.  In  the  case  of  a  bimolecular 
reaction,  halving  each  of  the  substances  will  cause  the 
amount  of  change  in  the  unit  of  time  to  be  reduced  to  one- 
quarter  of  its  previous  amount.  If  now  either  a  unimole- 
cular or  a  bimolecular  reaction  be  quickened  by  the  addition 
of  a  catalyser  or  ferment,  and  the  ferment  enter  into  com- 
bination with  one  of  the  substances  at  some  stage  of  the 
reaction,  it  is  evident  that  our  equation  must  take  account 
also  of  the  concentration  of  the  ferment  or  catalyser.  In  the 
case  of  the  catalytic  effect  of  molybdic  acid  on  the  interaction 
between  hydrogen  peroxide  and  HI,  which  w^e  studied  in  the 


2ii  THE    PHYSIOLOGY    OF    DIGESTION. 

last  lecture,  we  saw  that  there  was  definite  evidence  of  a 
reaction  taking  place  between  the  molybdic  acid  and  the 
peroxide,  resulting  in  the  formation  of  an  intermediate  com- 
pound, namely,  permolybdic  acid.  Erode  has  shown  that  the 
interaction  of  the  molybdic  acid  is  revealed  in  the  equation 
representing  the  velocity  of  the  reaction.  Without  the 
addition   of   molybdic   acid,   the   equation   would   be 

(i)  =  li  (Ch202  X  Chi)  • 
After  the  addition  of  the  molybdic  acid,  the  equation  becomes 

<^  =  K    (CH2O2  +  7.  CmdlyMic  acia)    ChI> 

where  y  is  another  constant  depending  on  the  molybdic  acid. 
If  the  ferments,  which  are  engaged  in  the  solution  of  the  food- 
stuffs, act  in  a  similar  way  by  the  formation  of  intermediate 
compounds,  this  fact  should  be  revealed  by  a  study  of  the 
velocity  at  which  the  ferment  action  takes  place. 

Various  methods  may  be  adopted  for  the  study  of  the 
velocity  of  ferment  in  action.  If,  for  instance,  we  were  inves- 
tigating the  action  of  diastase  upon  starch,  we  should  take 
solutions  of  starch  and  of  diastase  of  known  concentrations, 
keep  them  in  a  water  bath  at  38^  C,  or  whatever  temperature 
it  is  desired  to  study,  and  at  a  given  moment  add,  say,  20  cc. 
of  ferment  solution  to  every  100  cc.  of  the  starch  solution. 
At  periods  of  five  or  ten  minutes  after  the  addition  had  been 
made,  5  cc.  of  the  mixture  might  be  withdrawn  by  a  pipette  and 
at  once  run  into  boiling  Fehling's  solution.  The  precipitated 
cuprous  oxide  would  be  dried  and  weighed,  and  would  give 
directly  the  amount  of  sugar  formed  in  the  action  of  the 
ferment.  After  obtaining  a  series  of  data  in  this  way,  a 
curve  could  be  drawn,  showing  the  amount  of  change  of 
starch  which  had  occurred  in  each  unit  of  time.  In  the  case 
of  the  action  of  invertase  on  cane  sugar  the  investigation  is 
still  easier.  Since  the  change  from  cane  sugar  to  invert 
sugar  is  accompanied  by  a  change  in  the  rotatory  power  of 


THE    MODE    OF    ACTION    OF    FERMENTS.  23 

the  solution  on  polarised  light,  it  is  only  necessary  to  put  the 
mixture  of  ferment  and  cane  sugar  into  a  polarimeter  tube, 
which  is  kept  at  a  constant  temperature  by  means  of  a  water 
jacket,  and  read  off  at  intervals  of  a  few  minutes  the  change 
in  the  rotatory  power  of  the  solution.  From  this  change  can 
be  easily  calculated  the  percentage  of  cane  sugar  still  present, 
and  therefore  the  total  amount  which  has  been  converted  into 
fructose  and  glucose. 

The  question  of  the  velocity  of  reaction  becomes  more 
complex  when  we  deal  with  the  proteolytic  ferments,  owing  to 
the  immense  variety  of  products  which  result  from  the  breaking 
down  of  a  proteid  and  its  disintegration  in  successive  stages, 
albumoses  being  first  formed,  then  peptones,  and  finally 
amino-acids.  The  matter  is  still  further  complicated  by  the 
fact  that  these  stages  are  not  adhered  to  rigidly,  a  certain 
amount  of  amino-acids  being  formed  at  the  very  beginning 
of  the  reaction.  In  any  investigation,  however,  of  the  action 
of  proteolytic  ferments  such  as  pepsin  or  trypsin,  we  may 
take  any  given  alteration  of  proteid  and  observe  the  velocity 
with  which  it  occurs.  Thus,  if  we  are  studying  the  action  of 
trypsin  on  caseinogen,  we  can  take  samples  at  five-minute 
intervals  and  run  them  into  some  substance  such  as  trichlor- 
acetic acid,  which  will  precipitate  all  the  unchanged  proteid, 
i.e.,  caseinogen,  but  will  leave  in  solution  the  products  of 
hydration  of  the  proteid.  From  the  amount  of  nitrogen  in 
the  filtrate  from  the  precipitate  can  be  determined  the  total 
amount  of  proteid  which  has  undergone  hydration  in  the 
sample  under  observation.  Or  we  may  take  measured  por- 
tions at  intervals,  and  judge  of  the  amount  of  albumoses  and 
peptones  present  by  the  intensity  of  the  biuret  reaction  which 
can  be  obtained  in  each  sample.  This  method,  however, 
suffers  from  the  drawback  that  the  albumoses  and  peptones, 
at  any  rate  in  the  action  of  trypsin,  are  formed  merely  as  a 


24  THE    PHYSIOLOGY   OF    DIGESTION. 

stage  in  the  process,  and  the  intensity  of  the  reaction  will  first 
rise  to  a  maximum  and  then  gradually  disappear. 

In  the  process  of  proteolysis  there  is  a  breaking  down  of  the 
complex  colloid  molecules  into  a  large  number  of  simpler 
molecules.  The  colloidal  proteid  molecule  has  very  small 
conducting  power  for  electricity.  The  products  of  its  disinte- 
gration, namely,  albumoses  and  amino-acids,  belong  to  a  class 
of  bodies  known  as  the  amphoteric  electrolytes,  which  have  a 
conducting  power,  small  in  itself,  but  large  compared  with 
that  of  the  original  proteid  molecule.  Moreover,  in  the 
process  of  disintegration,  the  salts  which  are  absorbed  by  the 
colloidal  molecule,  and  therefore  not  free  to  exercise  their  con- 
ducting power,  are  set  free.  These  two  factors  together,  the 
production  of  smaller  molecules  and  the  setting  free  of  saline 
electrolytes,  account  for  the  rapid  rise  in  the  conductivity  of 
a  proteid  solution  when  it  is  subjected  to  hydrolysis.  The 
change  in  conductivity  can  be  used  as  a  means  of  judging  the 
rate  of  proteolysis.  This  method  presents  the  great  advantage 
that  a  continuous  series  of  readings  can  be  taken  without 
removing  the  solution  from  the  bath,  and  without  altering  in 
any  way  the  chemical  conditions  of  the  solution.  These  obser- 
vations may,  moreover,  be  quickly  carried  out,  so  allowing 
a  large  number  of  comparative  experiments  under  different 
conditions  to  be  made.  This  method  has  therefore  been 
employed  by  Bayliss  in  an  investigation  of  the  conditions 
which  determine  the  velocity  of  action  of  trypsin  on  solutions 
of  caseinogen. 

We  may  consider  first  those  experiments  in  which  the 
amount  of  trypsin  was  small  compared  to  the  amount  of 
substrate  (caseinogen).  In  this  case  it  was  found  that  the 
velocity  of  reaction  was  independent  of  the  concentration  of 
the  caseinogen  solution,  and  was  a  direct  linear  function 
of  the  amount  of  ferment  present.     This  is  shown  by  the 


THE    MODE    OF    ACTION    OF    FERMENTS. 


25 


experimental  results  in  the  following  table,  where  is  given 
the  effect  of  altering  the  concentration  of  the  ferment  on  the 
time  taken  for  the  hydrolysis  to  proceed  to  a  certain  point. 
The  point  chosen  was  the  time  taken  for  the  conductivity 
to  increase  to  350  gemmhos  (the  reciprocal  of  the  unit  of 
resistance,  megohm). 


Eelation  to 

Concentration  of  Trypsin. 

Trypsin. 

Time  of  equal  change. 

40 

3 

20 

6-5 

10 

10 

4 

40 

•  2 

75 

1 

150 

It  will  be  seen  that  the  time  taken  for  this  change  is  inversely 
proportional  to  the  concentration  of  the  ferment. 

The  same  result  has  been  observed  in  the  case  of  other 
ferments.  Thus  the  table  below  shows  the  results  obtained 
by  E.  F.  Armstrong*  on  the  hydrolysis  of  lactose  by  small 
quantities  of  lactase. 

Proportions  Hydrolysed  in  100  cc.  of  a  5  per  cent. 
Solution  of  Lactose. 


Solutions  containing — 

1"5  hours. 

20  hours. 

45  hours. 

1  CC.  lactase 

10  cc.     ,, 

20  cc.     „              

015 

1-6 
3-2 

2-2 
23-3 

45-8 

3-9 

38-6 

Here  again  the  amount  of  change  is  proportional  to  the 
amount  of  ferment  present.  The  same  observer  has  found 
that,  if  the  amount  of  substrate  is  very  large  compared  to  the 
ferment,  increasing  the  concentration  of  the  substrate  does 


"  Studies  on  Enzyme  Action."     Proc.  Eoy.  Soc.  Vol.  LXXIII.  pp.  500  et  seq. 


26 


THE    PHYSIOLOGY    OF    DIGESTION. 


not  increase  the  amount  hydrolysed,  i.e.,  a  given  quantity  of 
ferment  is  able  to  change  only  a  certain  amount  of  sugar  in 
a  given  time,  whatever  may  be  the  concentration  of  the  latter. 
This  is  shown  in  the  following  table  (Armstrong)  : — 

Amount  of  Sugar  (Lactose)  Hydrolysed. 


24  hours. 

46  hours. 

Proportion. 

Weight. 

Proportion. 

Weight. 

10  per  cent,  lactose 

20 

30 

14-2 
7-0 

4-8 

1-42 
1-40 
1-44 

22-2 
10-9 

7-7 

2-22 
2-18 
2-21 

Moreover,  if  we  take  only  the  earlier  stages  of  the  ferment 
action,  it  is  found  that,  with  small  proportions  of  ferment, 
equal  amounts  of  substrate  are  changed  in  successive  intervals 
of  time  until  about  10  per  cent,  has  been  hydrolysed.  This 
is  shown  in  the  following  table : — 

2  PER  CENT.  Lactose  with  Lactase. 

Time.  Amount  hydrolysed. 

i  hour 3-2 

6-4 
9-6 


1  „ 

2  hours 

3  „ 


16-4 
20-8 


Quite  a  different  result  is  observed  when  the  amount  of 
ferment  is  large  relatively  to  the  amount  of  substrate. 

Effect  of  Concentration  of  Substrate  (Bayliss). 

Caseinogen,  per  cent.  Change  in  20  minutes. 

385  gemmhos. 


4 

3-2 

2 

•8 
•4 


395 

200 

110 

10 


THE    MODE    OF    ACTION    OF    FERMENTS.  27 

Thus,  in  the  experiment  of  Bayliss  represented  here,  it 
will  be  noticed  that,  with  2  cc.  of  the  2  per  cent,  solution 
of  trypsin,  the  amount  of  change  in  twenty  minutes  was 
approximately  equal  in  a  3  per  cent,  solution  and  in  a  4  per 
cent,  solution  of  caseinogen.  On  diminishing  the  amount 
of  caseinogen  so  that  it  was  2,  "8,  and  '4,  he  found,  however, 
a  rapidly  lessening  amount  of  change  with  the  diminishing 
concentration  of  the  caseinogen.  This,  of  course,  is  what 
one  would  expect  either  in  a  unimolecular  or  bimolecular  re- 
action ;  but  if  a  series  of  observations  are  made  at  intervals 
of  ten  minutes  on  a  mixture  containing  caseinogen  and  a 
proportionately  large  amount  of  ferment,  it  will  be  seen  that 
there  is  a  rapid  diminution  of  the  rate  of  change  from  the 
very  beginning.  This  is  shown  in  the  table  below,  in  which 
the  velocity  constant  K  has  been  calculated  from  a  series  of 
observations. 

Velocity  of  Trypsin  Reaction. 

N 
6  cc.  8  per  cent,  casemogen  +  2  cc.  —  AiiiHO  +  2  cc.  2  per  cent. 


tr3'psin  at  39° 

C. 

1st  10  mmutes 

K  =  00079 

2nd 

0-0046 

3rd 

•0032 

4th 

•0022 

5th 

•0016 

7th 

•0009 

Etc. 

Etc. 

Whereas  in  an  ordinary  chemical  reaction,  such  as  those 
mentioned  at  the  beginning  of  this  chapter,  K  remains  con- 
stant throughout  the  reaction,  here  we  see  a  rapid  diminution 
in  this  factor. 

How  are  we  to  account  for  the  results  obtained  with  small 
and  large  quantities  of  ferment  respectively  ?  The  experi- 
ments made  on  small  quantities  of  ferment  can  only  be 
interpreted  by  assuming  that  the  first  stage  in  the  reaction 


28  THE    PHYSIOLOGY    OF    DIGESTION. 

is  a  combination  of  ferment  with  substrate.  It  is  only  this 
compound  which  represents  the  active  mass  of  the  molecules, 
i.e.,  the  molecules  of  substrate  which  are  undergoing  change. 
This  compound,  as  soon  as  it  is  formed,  takes  up  water  and 
breaks  down,  setting  free  the  hydrolysed  substrate  and  the 
ferment,  which  is  at  once  ready  to  combine  with  a  further 
portion  of  the  substrate.  In  such  a  case  the  velocity  of 
reaction  must  be  directly  proportional  to  the  amount  of  fer- 
ment, and  the  same  absolute  quantity  of  substance  will  con- 
tinue to  be  changed  in  succeeding  units  of  time.  Supposing, 
for  instance,  we  had  at  the  bottom  of  a  hill  a  load  of  bricks 
which  had  to  be  transferred  to  the  top,  and  five  men  to  effect 
the  transference.  The  rate  of  transference  would  be  directly 
proportional  to  the  number  of  men  employed ;  we  could 
double  the  rate  by  doubling  the  men.  Moreover,  the  number 
of  bricks  carried  in  each  unit  of  time  would  be  the  same. 
Five  men  would  carry  as  many  bricks  in  the  second  ten 
minutes  as  they  would  in  the  first,  and  so  on.  On  the  other 
hand,  the  velocity  with  which  the  transference  was  effected 
would  be  independent  of  the  number,  that  is,  the  concentra- 
tion of  the  bricks  at  the  bottom  of  the  hill.  The  active  mass 
of  bricks  could  be  regarded  as  that  number  carried  at  any 
moment  by  the  transferring  factor,  namely,  the  men.  The 
equation  of  change  .would  be  <^  =  K  C,  where  C  is  the  con- 
centration of  the  ferment.  This  concentration  is  always 
being  renewed,  and  kept  constant  by  the  breaking  down  of 
the  intermediate  product,  so  that  the  rate  of  change  would  be 
continuous  throughout  the  experiment. 

The  condition  of  things  which  obtains  when  the  amount  of 
ferment  is  largely  increased  is  more  difficult  to  interpret. 
The  rajDid  diminution  in  the  velocity  of  change  may  be  caused, 
in  part  at  least,  by  the  autodestruction  of  the  ferment.  All 
these   ferments  are   unstable    bodies,  and   tend   to    undergo 


THE    MODE    OF    ACTION    OF    FERMENTS.  29 

disintegration  in  watery  solutions.  That  this  is  not  the 
most  important  factor,  however,  is  shown  by  the  fact  that, 
when  the  action  of  trypsin  on  caseinogen  has  apparent!}'  conib 
to  an  end,  it  may  be  renewed  by  further  dikition  of  the 
mixture  or  by  removal  of  the  end  products  of  the  action  by 
dialysis.  It  is  evident  that,  in  this  retardation  of  the  later 
stages  of  ferment  action,  the  end  products  are  concerned  in 
some  way  or  other,  and  the  retardation  can  be  augmented  by 
adding  to  the  digesting  mixture  the  boiled  end  products  of  a 
previous  digestion.  The  retarding  effect  of  the  end  products 
resembles  in  many  ways  that  observed  in  a  whole  series  of 
reactions  which  are  known  as  reversible.  As  an  example  of 
such  a  reaction  we  may  take  the  case  of  methyl  acetate  and 
water.  When  methyl  acetate  is  mixed  with  water  it  undergoes 
decomposition  with  the  formation  of  methyl  alcohol  and  acetic 
acid.  On  the  other  hand,  if  acetic  acid  be  mixed  with  alcohol, 
an  interaction  takes  place  with  the  formation  of  methyl  acetate 
and  water.  These  changes  are  represented  by  the  equation 
Me  C2H3O2  +  HOH  ;1  Me  OH  +  HC2H3O2.  Each  of  these 
changes  has  a  certain  velocity  constant,  and,  since  they  are  in 
opposite  directions,  there  must  be  some  equilibrium  point 
where  no  change  will  occur,  and  where  there  will  be  a  certain 
definite  amount  of  all  four  substances  present  in  the  mixture, 
namely,  water,  alcohol,  ester,  and  acid.  This  equilibrium 
point  can  be  altered  by  altering  the  amount  of  any  of  the  four 
substances.  Thus  the  interaction  of  methyl  acetate  and  water 
can  be  diminished  to  any  desired  extent  b}"  adding  to  the 
mixture  the  products  of  the  interaction,  namely,  methyl 
alcohol  and  acetic  acid. 

The  question  at  once  arises  whether  we  have  in  the  action 
of  ferments  a  similar  reversible  phenomenon.  There  is 
evidence  that  some  of  the  ferment  actions  are  reversible. 
Thus   maltase   acts   on   maltose  with  the  formation   of   two. 


30  THE    PHYSIOLOGY    OF    DIGESTION. 

molecules  of  dextrose.  If,  however,  the  maltase  be  added  to  a 
concentrated  solution  of  dextrose,  we  get  a  reverse  effect,  with 
the  production  of  a  disaccharide  which  has  been  designated 
as  isomaltose  or  revertose.  The  addition  of  the  proteolytic 
ferment,  pepsin,  to  a  strong  solution  of  albumose  and  peptone 
causes  the  appearance  of  a  precipitate,  which  has  been  called 
plastein,  and  is  probably  due  to  a  reaggregation  of  •  the  albu- 
mose and  peptone  molecules  which  had  been  separated  by 
the  process  of  hydrolysis.  It  is  possible  that  to  this  reverse 
action  is  due  a  certain  amount  of  the  retardation  observed 
in  the  action  of  trypsin  on  coagulable  proteid.  It  is  pro- 
bable, however,  that  another  factor  is  involved  and  is  the 
more  important  of  the  two,  namely,  the  combination  of  the 
ferment  itself  with  the  end  products,  and  the  consequent 
removal  of  the  ferment  from  the  sphere  of  action.  Several 
facts  speak  for  such  a  mode  of  explanation.  Thus  the  action 
of  lactase  on  milk  sugar  is  not  retarded  by  both  its  end 
products,  namely,  glucose  and  galactose,  but  only  by  galactose. 
In  the  same  way  the  action  of  invertase  on  cane  sugar  is 
retarded  by  the  end  product  fructose,  but  not  at  all  by  the 
other  end  product,  glucose.  The  effect  of  trj^psin  on  proteids 
is  retarded  not  only  by  the  end  products  of  its  own  reaction, 
but  also  by  the  addition  of  various  end  products  derived 
from  the  action  of  proteolytic  ferments  on  other  proteids. 

So  far,  therefore,  a  study  of  the  velocity  of  ferment  actions 
would  lead  us  to  suspect  that  the  ferment  combines  in  the 
first  place  with  the  substrate,  and  that  this  combination  is 
a  necessary  step  in  the  alteration  of  the  substrate.  In  the 
second  place,  the  ferment  is  taken  up  to  a  certain  extent  by 
some  or  all  of  the  end  products,  and  this  combination  acts  in 
opposition  to  the  first  combination,  tending  to  remove  the 
ferment  from  the  sphere  of  action,  and  therefore  to  retard  the 
whole  reaction.    Other  facts  can  be  adduced  in  favour  of  these 


THE    MODE    OF    ACTION    OF    FERMENTS.  31 

conclusions.  Thus  it  has  been  shown  that  invertase  ferment, 
which  is  destroyed  when  heated  in  watery  sokition  at  a 
temperature  of  60°  C,  can,  if  a  large  excess  of  its  substrate, 
cane  sugar,  be  present,  be  heated  25°  higher  without  under- 
going destruction.  The  same  protective  effect  is  observed  in 
the  case  of  trypsin.  Trypsin  in  watery  or  weakly  alkaline  solu- 
tions undergoes  rapid  decomposition.  At  37°  C.  it  may  lose 
50  per  cent,  of  its  proteolytic  power  within  half  an  hour.*  If, 
on  the  other  hand,  trypsin  be  mixed  with  a  proteid  such  as 
egg-albumin  or  caseinogen,  or  with  the  products  of  its  own 
action,  namely  albumoses  and  peptones,  it  can  be  kept  many 
hours  without  undergoing  any  considerable  loss  of  power. 

Another  fact,  which  tells  in  favour  of  some  form  of 
combination  between  ferment  and  substrate,  is  the  specificity 
of  the  ferment;  i.e.,  each  ferment  will  act  only  on  a  class 
of  bodies  grouped  together  by  their  chemical  composition, 
and  especially  by  the  stereochemical  configuration  of  their 
molecules.  In  the  table  on  next  page  is  drawn  up  a  list 
of  four  ferments,  with  the  substances  with  which  they  can 
combine.! 

In  this  list  it  will  be  seen  that,  whereas  maltase  splits  up  all 
the  a-glucosides,  it  has  no  power  on  the  yS-glucosides  ;  that  is 
to  say,  maltase  will  fit  into  a  molecule  of  a  certain  configura- 
tion, but  is  powerless  to  affect  a  molecule  which  differs  only 
from  the  first  in  its  stereochemical  structure.  On  the  other 
hand,  emulsin,  which  breaks  up  /3-glucosides,  has  no  influence 
on  a-glucosides. 

This  specific  affinity  of  the  ferments  for  optically  active 
groups  of  bodies  suggests  that  the  ferment  itself  may  be 
optically  active.     We  cannot  of  course  isolate  the  ferment  and 


*  Cp.  Vernon,  Journ.  of  Phijsiol.  Vol.  XXVIII.  p.  448,  1902. 
t  E.  F.  Armstrong,  loc.  cit,  p.  520. 


32 


THE    PHYSIOLOGY    OF    DIGESTION. 


determine  its  optical  behaviour,  but  that  it  is  optically  active 
is  rendered  probable  both  by  these  results  and  by  certain 
results  obtained  by  Dakin  *  on  lipase,  the  fat-splitting  ferment. 
Dakin  carried  out  his  experiments  on  the  esters  of  mandelic 
acid.  Mandelic  acid  is  optically  inactive,  but  this  optically 
inactive  modification  consists  of  a  mixture  of  equal  parts  of 
dextro-rotatory  and  Isevo-rotatory  mandelic  acid.     The  esters 


Enzj'me. 

Corresponding  liydrolyte. 

Effect  of  liexose  on  rate  of  change. 

Glucose. 

Galactose. 

Fructose. 

Lactase. 

Emulsin. 

Maltase. 

Invertase. 

/3  -  galactosides,      milk 
sugar ;    )3-aIkylgalac- 
tosides. 

/8-glucosides      (most 
natural   glucosides)  ; 
8-galactosides. 

a-glucosides,     maltose, 
and  a-alkylglucosides; 
a-galactosides      [i.e., 
a-alkylgalactosides). 

Fructosides;    cane 
sugar;    raffinose; 
gentianose. 

No 
influence. 

Retards 
consider- 
sh\y. 

Retards 
consider- 
ably. 

No 
influence. 

Retards. 

Retards 
slightly. 

Retards 

slightly. 

No 
influence. 

No 
influence. 

No 
influence. 

Retards. 

prepared  from  the  optically  inactive  acids  are  themselves 
optically  inactive.  Dakin  found  that,  when  an  optically 
inactive  mandelic  ester  was  acted  upon  by  a  lipase  prepared 
from  the  liver,  the  final  results  of  the  action  were  also  inactive; 
but  if  the  reaction  were  interrupted  at  the  half-way  point,  the 
mandelic  acid  which  had  been  liberated  was  dextro-rotatory, 
while  the  remainder  of  the  ester  was  laevo-rotatory.  Thus 
the  rate  of  hydrolysis  of  the  dextro-component  of  the  ester 
is   greater  than  that  of  the  Isevo-component,  a  result  which 


Dakin,  Journ,  of  Physiol.  Vol.  XXXII.  p.  199,  1905. 


THE    MODE    OF    ACTION    OF    FERAIENTS.  33 

can  be  best  explained  by  the  assumptions  (a)  that  the  enzyme 
or  a  substance  closely  associated  with  it  is  a  powerfully 
optically  active  substance ;  (h)  that  actual  combination  takes 
place  between  the  enzyme  and  the  ester  undergoing  hydrolysis. 
Since  the  additive  compounds  thus  formed  in  the  case  of  the 
dextro-  and  l?evo-components  of  the  ester  would  not  be  optical 
opposites,  they  would  be  decomposed  with  unequal  velocity, 
and  thus  account  for  the  liberation  of  the  optically  active 
mandeUc  acid. 

The  scanty  evidence,  which  we  have  as  to  the  composition 
of  ferments,  would  seem  to  point  to  a  chemical  similarity 
between  ferment  and  substrate.  Thus,  in  the  case  of  invertase, 
Osborne  *  found  that  it  had  the  composition  of  a  carbohydrate 
■with  a  nitrogenous  group  introduced.  This  similarity  of 
structure  between  ferment  and  substrate  is  further  supported 
by  the  results  just  mentioned  as  to  the  specific  effect  of 
closely  related  substances  in  inhibiting  or  retarding  the  action 
of  the  ferment  (see  table  p.  32),  e.g.,  the  fact  that  the  action 
of  lactase  is  retarded  by  galactose,  but  is  uninfluenced  by 
glucose  or  fructose.  We  may  conclude  that,  in  the  action  of 
ferments  on  the  food  substances,  whether  carbohydrate  or 
proteid,  an  essential  factor  is  the  combination  of  the  ferment 
with  the  substrate,  and  it  is  only  the  part  of  the  substrate, 
which  is  thus  in  combination  or  in  relation  with  the  ferment, 
which  can  be  regarded  as  the  active  mass  and  as  undergoing 
the  hydrolytic  change. 

These  ferments  however  cannot  be  dealt  with  in  the  same 
'svay  as  the  definite  chemical  substances  such  as  molybdic 
acid.  All  of  them  are  of  a  colloid  or  semi-colloid  nature,  and  it 
is  impossible  to  assign  to  them  a  chemical  formula,  or  to  form 
any  idea  of  the  actual  number  or  condition  of  the  molecules 

*  Osborne,  "  Zeitsch.  f.  Physiol.  Chem.,"  XXVIII.,  p.  399,  1899. 
P.D.  D 


84  THE    PHYSIOLOGY    OF    DIGESTION. 

involved  in  the  reaction.  In  many  cases  too  the  substrate, 
e-g.,  starch  and  proteid,  is  also  of  a  colloidal  character,  and  we 
have  therefore  to  consider  the  form  of  interaction  which  can 
occur  between  such  colloidal  substances,  and  will  nevertheless 
be  specific  and  display  the  limited  affinities  of  each  body 
concerned. 

To  the-  relationship  between  ferment  and  substrate  we  have  a 
close  analogy  in  that  between  toxin  and  antitoxin,  or  between 
lysin  and  antilysin,  etc.  As  examples  of  toxins  we  may  take 
diphtheria  and  tetanus  toxin.  These  are  substances  produced 
in  the  living  bacilli  and  excreted  by  them  into  the  surround- 
ing medium.  When  introduced  into  the  body,  they  cause 
injury  in  various  w^ays,  generally  by  affecting  the  vital  activity 
of  some  special  tissue  or  class  of  tissues.  If  small  doses  be 
injected  into  the  body,  they  give  rise  to  the  production  in 
the  blood  serum  of  an  antitoxin,  i.e.,  of  a  substance  which 
not  only  has  the  power  of  inhibiting  the  poisonous  effect  of 
fresh  doses  of  toxin,  but  can  be  added  to  the  toxin  in  vitro 
and  neutralise  its  effect  when  injected  into  other  animals. 
A  close  similarity  exists  between  toxins  and  various  other 
substances  which  are  produced  by  bacteria  and  other  living 
organisms.  Thus  the  filtered  extracts  of  tetanus  or  diphtheria 
bacilli,  besides  the  specific  toxins,  contain  bodies  which  have 
a  hgemolytic  action  and  are  spoken  of  as  hsemolysins. 
Similar  hsemolytic  substances  are  contained  in  the  venom  of 
snakes,  in  abrin  (the  poisonous  proteid  obtained  from  the 
plant  jequirity),  and  in  the  filtered  culture  fluid  from  a  species 
of  bacillus,  namely.  Bacillus  megatherium.  The  injection  of 
haemolysins  into  the  circulation  of  an  animal,  in  gradually 
increasing  doses,  gives  rise  to  the  appearance  in  the  blood 
serum  of  an  antilysin. 

The  most  usual  conception  of  the  action  of  these  bodies,  a 
conception  which  we  owe  to  Ehrlich,  is  that  they  consist  of  a 


THli    MODE    OF    ACTION    OF    FERMENTS.  35 

centrally  placed  proteid  group  with  two  side  chains,  one  of 
which  by  its  stereomeric  configuration  is  peculiarly  adapted 
to  fit  on  to  the  organ  or  cell  of  the  body  which  the  toxin  or 
active  body  attacks,  and  is  known  as  the  haptophore  group, 
and  another  side  chain,  the  toxophorc  group,  which  is  respon- 
sible, w^hen  the  toxin  is  once  anchored,  for  the  destructive 
changes  wrought  by  the  toxin  on  the  cell  of  the  body.  The 
antitoxins  or  antilysins  are  thus  supposed  to  act  in  virtue  of 
their  adaptation  to  the  haptophore  group,  so  as  to  combine 
with  the  toxin  or  lysin  and  prevent  these  exercising  their 
injurious  effects  on  the  body.  Ehrlich  has  shown  that  in 
many  toxins  the  toxophore  group  can  undergo  weakening  or 
destruction  without  any  alteration  of  the  haptophore  group  ; 
such  modifications  he  designates  as  toxoids.  They  have  the 
same  combining  power  for  antitoxins  as  is  possessed  by  the 
ordinary  toxin,  but  are  either  without  physiological  effect,  or 
their  poisonous  characters  are  only  a  fraction  of  that  possessed 
by  ordinary  toxin.  It  seems  probable  that  in  the  case  of 
enzymes  we  have  also  to  deal  with  similar  relationships.  We 
may  conceive  that  the  ferment  fits  on,  as  we  have  seen  really 
happens,  by  means  of  its  haptophore  group.  The  specificity  of 
the  enzyme  is  therefore  a  function  of  its  haptophore  group.  The 
changes  it  effects  in  the  substrate  would  be  due  to  a  zymophoi-e 
group.  As  in  the  case  of  toxins,  this  zymophore  group  may 
undergo  alteration  or  destruction  without  the  haptophore  group, 
and  modifications  of  enzymes  may  be  produced  by  heating  or 
other  means,  resulting  in  the  production  of  a  substance  w^hich 
may  be  termed  zymoid.  Thus  Bayliss  has  shown  that  trypsin 
on  warming,  or  under  the  action  of  strong  acid,  is  converted 
into  a  modification  which  has  much  less  proteolytic  power 
than  ordinary  trypsin,  but  still  possesses  the  powder  of  binding 
certain  molecules  of  the  substrate.  This  combining  effect 
is   shown  by  the  fact  that  the  addition  of  the  zymoid  to  a 

D  2 


86  THE    PHYSIOLOGY    OF    DIGESTION. 

proteid  solution  causes  a  preliminary  fall  in  the  conductivity 
of  the  whole  solution.  It  has  been  shown  moreover  by 
Korschun,  that  from  rennin  ferment  it  is  possible,  by  filtra- 
tion through  a  clay  filter,  to  separate  a  part  which  has  less 
coagulating  power  on  milk  than  ordinary  rennin,  but  has  the 
same  power  of  neutralising  an  anti-rennin  serum  produced  by 
the  injection  of  rennin  into  the  veins  of  an  animal. 

The  question  of  the  manner  in  which  the  antitoxin  is  able 
to  combine  with  and  neutralise  the  toxin  is  one  of  consider- 
able practical  importance.  In  this  process  we  have  relations 
presenting  marked  analogies  with  the  neutralisation  of  acids 
by  bases.  If  we  define  a  unit  of  toxin  as  that  amount  which 
possesses  a  certain  power,  i.e.,  which  will  kill  a  guinea-pig  in 
so  many  days,  or  will  cause  the  complete  hgemolysis  of  1  cc. 
of  blood  in  two  and  a  half  hours,  we  can  find  the  amount  of 
anti-body  which  is  just  sufficient  to  neutralise  this  effect, 
and  this  amount  of  anti-body  can  be  regarded  also  as 
one  unit.  If  instead  of  one  unit  of  each  we  take  100  units, 
the  neutralisation  is  effected  in  the  same  way.  The  process 
is  found,  however,  to  be  more  complex  when  we  take 
100  units  of  toxin  or  lysin,  and  attempt  to  neutralise  them  by 
the  fractional  addition  of  antitoxin.  In  the  case  of  a  strong 
acid  and  strong  alkali  we  know  that,  if  100  cc.  of  alkali  are 
just  sufficient  to  neutralise  100  cc.  of  acid,  the  addition  of 
60  cc.  of  alkali  will  leave  half  the  acid  unneutralised.  If, 
however,  we  try  the  same  experiment  in  the  case  of  mixtures 
of  toxin  and  antitoxin,  it  will  be  found  that  the  addition  of 
50  cc.  of  antitoxin  will  neutralise  much  more  than  half  of 
the  toxin,  and  the  same  applies  with  other  bodies  of  this  class. 
As  an  example,  we  may  take  the  relation  between  a  standard 
suspension  of  typhoid  bacilli  and  a  serum  which  has  the 
power  of  agglutinating  typhoid  bacilli.  In  the  table  given 
below  are  represented  the  results  of  the  addition  of  varying 


THE    MODE    OF    ACTION    OF    FERMENTS. 


37 


units  of  agglutinating  serum  to  a  suspension  of  bacilli.  It 
will  be  seen  that  the  amount  taken  up  by  the  bacilli  is  not  a 
definite  quantity,  but  is  determined  by  the  concentration  of 
the  agglutinating  solution. 


Effects   of  Adding  Various  Dilutions   of  Agglutinating  Serum  to 
Equal  Volumes  of  a  Suspension  of  Typhoid  Bacilli.     (Craw.) 


Concentration 
of  Serum. 

Units  of  agglutinin 
added. 

Units  of  agglutinin 
absorbed. 

Units  of  agglutinin 
free. 

1/20 

2000 

1300 

730 

1/30 

1333 

1133 

200 

1/40 

1000 

840 

160 

1/60 

666 

646 

20 

1/200 

200 

200 

0 

Ehrlich  has  attempted  to  explain  this  result  by  assuming 
that  in  any  toxin  there  is  a  mixture  of  substances,  some 
having  a  strong  affinity  for  the  antitoxin,  and  others, 
which  he  calls  toxones,  possessing  only  a  slight  affinity.  In 
the  50  cc.  of  toxin  first  added,  the  toxins  would  satisfy 
all  their  combining  powers,  whereas  the  toxones  would  not 
begin  to  combine  until  they  w^ere  present  in  large  excess. 
Arrhenius  and  Madsen  have  drawn  an  analogy  between  the 
neutralisation  of  toxin  by  antitoxin  and  the  neutralisation  of 
a  weak  acid,  such  as  boracic  acid,  by  a  weak  base,  such  as 
ammonia.  They  show  that  in  this  case  the  general  course  of 
events  would  be  similar  to  that  observed  by  Ehrlich.  At  no 
time  would  there  be  complete  neutralisation,  owing  to  the 
fact  that  hydrolysis  constantly  occurs,  so  that,  when  equivalent 
quantities  of  each  substance  had  been  added,  the  fluid  would 
still  contain  a  certain  amount  of  free  base  alongside  of  free 


38  THE    PHYSIOLOGY   OF    DIGESTION. 

acid,  in  addition  to  the  salt  produced  by  the  combination  of  the 
two.  It  is  inijDOSsible,  however,  to  account  for  all  the  pheno- 
mena presented  in  the  neutralisation  of  toxin  by  antitoxin 
in  this  simple  manner.  Thus  the  results  given  in  the  above 
table  could  not  be  explained  on  any  hypothesis  of  chemical 
combination.  Seventeen  parts  of  ammonia  would  neutralise 
exactly  an  equivalent  quantity  of  boracic  acid,  whether  these 
substances  were  dissolved  in  10  cc.  or  in  100  cc.  of  water. 
If,  however,  it  be  found  that  1  cc.  of  antilysin  exactly 
neutralises  1  cc.  of  lysin,  these  two  substances  will  no 
longer  be  in  equilibrium  when  the  whole  is  diluted  up  to 
10  cc.  with  water.  If  a  neutral  mixture  of  lysin  and 
antilysin  be  taken  and  filtered  under  pressure  through 
a  gelatin  filter,  no  lysin  or  antilysin  passes  through 
the  filter,  so  that  the  residue  on  the  filter  becomes  con- 
centrated. On  examining  this  residue  it  is  found  that  it 
has  a  strong  hsemolytic  action,  and  the  same  is  true  of  the 
substance  which  may  be  obtained  by  melting  the  gelatin  out 
of  the  pores  of  the  filter.  It  is  evident  that,  even  in  a  neu- 
tralised mixture,  both  free  lysin  and  free  antilysin,  or  free  toxin 
and  free  antitoxin  are  present,  and  it  needs  only  the  alteration 
of  the  physical  conditions  of  the  mixture  in  order  to  display 
the  action  of  one  or  other  of  these  bodies.  How  then  are  we 
to  regard  this  combination  of  toxin  with  antitoxin  ?  Craw 
points  out  that  the  combination  is  in  all  respects  comparable 
to  that  which  occurs  between  adsorbing  surfaces  and  many 
dye-stuffs.  If  we  place  some  filter  paper  in  a  solution  of 
fuchsin  or  Congo  red,  the  filter  paper  will  take  up  a  large 
amount  of  the  dye  substance.  The  amount  taken  up  by  the 
paper  will  increase  with  increase  in  concentration  of  the 
solution.  There  will,  however,  be  a  tendency  to  the  formation 
of  false  equilibrium  points,  as  in  the  case  of  the  reaction  of 
toxin  and  antitoxin.     Thus  if  two  solutions  of  fuchsin  be  made, 


THE    MODE    OF   ACTION    OF    FERMENTS.  89 

and  to  each  a  sheet  of  filter  paper  be  added,  but  in  one  case 
the  paper  be  added  at  once,  in  the  other  case  in  three  parts 
at  intervals  of  twelve  hours,  at  the  end  of  thirty-six  hours 
the  paper  which  has  been  added  in  parts  will  have  removed 
more  dye-stuff  from  the  solution  than  is  the  case  where  the 
whole  amount  of  paper  was  added  at  once.  In  the  same  way, 
,when  treating  a  suspension  of  bacilli  with  an  agglutinating 
serum,  it  is  found  that  the  successive  addition  of  the  bacil- 
lary  suspension  to  the  serum  removes  more  agglutinin  from 
the  solution  than  when  the  addition  is  made  at  one  time. 

The  interactions,  therefore,  between  these  bodies  must  be 
looked  upon  as  special  examples  of  the  group  of  phenomena 
known  as  adsorption,  such  as  the  adsorption  of  iodine  from 
solutions  by  charcoal,  of  iodine  from  water  by  starch,  or 
of  ammonia  by  charcoal. 

Is  the  combination  between  ferment  and  substrate  of  the 
same  nature?  Though  it  is  impossible  to  give  a  decisive 
answer  to  this  question  at  the  present  time,  it  seems  probable 
that  the  specific  combination  of  ferments  with  certain  definite 
substrates  is  in  all  respects  analogous  to  the  combination  of 
toxin  or  lysin  with  their  corresponding  anti-body,  and  it  is 
noteworthy  that  the  assumption  of  the  colloidal  condition — a 
condition  in  which  there  is  an  enormous  exaggeration  of 
surface — seems  to  be  an  important  condition  in  deciding  the 
catalytic  effect  of  any  given  substance.  Thus  platinum,  which, 
in  the  metallic  state,  has  a  marked  power  of  condensing 
oxygen  and  hydrogen  on  its  surface,  has  also  a  strong  catalytic 
action.  The  same  catalytic  power  can  be  imparted  to  other 
metals  such  as  gold,  silver,  lead,  cadmium,  or  silver,  by  bringing 
them  into  colloidal  solution.  As  Bredig  has  shown,  the 
passage  of  a  small  arc  between  metallic  wires  under  distilled 
water  leads  to  the  metal  being  thrown  off  in  clouds  of 
fine  ultra-microscopic   particles,  which   remain  in   perpetual 


40  THE    PHYSIOLOGY    OF    DIGESTION. 

suspension  in  the  fluid.  The  '  sol '  thus  obtained  has  all  the 
properties  of  a  colloidal  solution,  and  it  shares  with  platinum 
'  sol '  the  j)Ower  of  quickening  various  chemical  processes, 
especially  the  decomposition  of  hydrogen  peroxide.  We  know 
that  the  molecules  which  are  in  immediate  contact  with  a 
surface  are  in  a  different  condition  of  aggregation,  and  the  mere 
exaggeration  of  surface,  which  occurs  in  these  colloidal  solutions, 
seems  to  be  sufficient  to  bring  a  large  number  of  molecules 
into  the  condition  in  which  they  are  able  to  interact  chemically, 
and  so  hasten  any  chemical  interaction  which  would  otherwise 
go  on  with  an  extremely  slow  velocity.  This  influence  of 
surface  is  not,  however,  absolutely  general.  Even  platinum 
'  sol '  is  not  a  universal  catalyser,  and  although  in  every  case 
we  must  regard  adsorption  by  a  surface  as  the  essential 
factor,  the  exact  adsorption  which  takes  place  is  evidently  a 
function  of  the  chemical  configuration  of  the  substance  forming 
the  surface.  We  cannot  otherwise  account  for  the  specific 
interaction  between  toxins  and  antitoxins,  or  for  the  specific 
action  of  the  different  ferments  on  their  various  substrates. 
We  have  here,  therefore,  a  special  class  of  interactions,  not 
entirety  chemical  and  not  entirely  physical,  but  depending  for 
their  existence  on  a  co-operation  of  both  chemical  and  physical 
factors.  To  definitely  assign  ferment  actions  to  this  class, 
would  be  premature.  There  is,  indeed,  evidence  that  ferments 
act  on  the  substrate  by  forming  intermediate  combinations 
with  it,  but  whether  these  compounds  are  to  be  regarded  as 
chemical  or  as  adsorptive  we  have  not  yet  sufficient  evidence  to 
determine.  The  facts  that  the  ferments  all  belong  to  the 
class  of  imperfect  colloids,  and  that  in  many  cases,  e.g, 
proteolytic  ferments  and  diastase,  their  action  is  on  complete 
colloids,  would  certainly  suggest  that  the  combinations  must 
be  of  the  physical  type. 


LECTUEE    III. 

SECRETION    OF    SALIVA. 

The  taking  of  food  into  the  mouth  is  at  once  followed  by  the 
pouring  out  of  a  large  quantity  of  saliva  into  this  cavity. 
This  fluid  is  the  product  of  secretion,  partly  of  a  multitude  of 
small  glands  scattered  over  the  surface  of  the  tongue  and  the 
mucous  membrane  forming  the  lining  of  the  mouth  cavity, 
but  to  a  larger  extent  of  three  pairs  of  salivary  glands  which 
pour  their  fluid  into  the  mouth  by  means  of  long  tubes  or 
ducts.  These  glands  are  the  parotid,  the  submaxillary,  and 
the  sublingual.  The  fluid  which  moistens  the  food  is  there- 
fore a  mixture  of  the  secretions  of  these  various  glands.  Its 
average  composition  has  been  given  by  Maly  as  follows  : — 

Water           992-9 

Total  solids             7-1 

Suspended  solids  (epithelium,  mucus,  etc.)       .  .          .  .  1*4 

Soluble  organic  matter  (chiefly  proteid  and  mucin)     .  .  3-8 

Inorganic  salts        .  .          .  .          .  .          .  .                      . .  1"9 

The  composition,  however,  varies  according  to  the  nature  of 
the  food  which  has  been  taken  in. 

The  use  of  this  admixture  of  food  with  saliva  is  chiefly 
mechanical.  The  saliva  not  only  moistens  the  food  and  thus 
aids  its  mastication  by  the  teeth,  but  also,  in  virtue  of  the 
mucin  that  it  contains,  lubricates  all  the  passages,  and  so 
facilitates  the  process  of  swallowing,  and  the  passage  of  the 
food  bolus  into  the  stomach.  In  dogs  the  mechanical  action 
of  saliva  is  its  only  one.     In  herbivora  and  in  omnivora,  such 


42  THE    PHYSIOLOGY    OF    DIGESTION. 

as  man,  the  saliva  has  a  further  action,  and  is  an  important 
agent  in  the  digestion  of  starch.  The  saliva  secreted  by  the 
parotid  gland  contains  an  amylase  known  as  ptyalin.  Under 
the  action  of  this  ferment,  boiled  starch  is  transformed  into 
dextrin  and  maltase.  It  might  be  thought  that  the  stay  of  the 
food  in  the  mouth  is  of  too  short  duration  to  admit  of  any 
appreciable  degree  of  starch  solution  taking  place.  The 
action  of  saliva  is  not,  however,  confined  to  the  period  that 
the  food  remains  in  the  mouth.  When  a  meal  is  taken,  the 
food,  after  mastication,  is  swallowed  in  a  succession  of  boluses, 
and  collects  in  a  mass,  moistened  throughout  with  saliva,  in 
the  stomach.  It  is  true  that  the  taking  of  food  determines 
the  pouring  out  of  an  acid  juice  in  the  stomach,  a  juice  which 
not  only  prevents  the  digestive  action  of  ptyalin  but  actually 
destroys  this  ferment.  It  takes,  however,  a  considerable  time 
for  this  acid  gastric  secretion  to  penetrate  the  mass  of  food 
lying  in  the  stomach,  and  the  saliva  in  the  interior  of  the 
mass  has  from  twenty  to  forty  minutes  at  its  disposal  to  act 
on  the  starchy  constituents  of  the  food,  before  the  acid  gastric 
juice  can  penetrate  and  destroy  the  ptyalin.  The  main 
digestive  action  of  saliva  therefore  occurs  in  the  stomach. 

The  mixed  saliva,  whose  composition  I  have  given  above,  is 
the  product  of  secretion  of  the  different  glands,  and  is  composed 
of  fluids  which  vary  in  their  composition  according  to  the 
gland  from  which  they  are  derived,  and  according  to  the 
conditions  which  have  determined  the  activity  of  the  gland. 
Thus  the  saliva  obtained  from  the  parotid  gland  contains 
water,  salts,  traces  of  albumin  and  globulin,  and  in  many 
animals  ptyalin.  Mucin  is  however  absent.  On  the  other 
hand,  the  secretion  of  the  submaxillary  gland,  especially  in  the 
dog,  consists  essentially  of  a  solution  of  mucin  in  a  weak  salt 
solution.  This  secretion  can  vary  considerably  in  quality 
according  to  the  conditions  determining  the   activity  of  the 


SECRETION    OF    SALIVA.  43 

gland.  Thus  by  a  suitable  admixture  of  these  various  secre- 
tions it  is  possible  to  adapt  the  saliva  to  the  nature  of  the  food 
in  the  mouth.  In  order  to  determine  the  nature  of  the  saliva 
which  is  poured  into  the  mouth  in  response  to  the  physiolo- 
gical stimuli  of  various  kinds  of  food,  the  best  method  is  to 
divert  the  ducts  of  the  submaxillary  and  parotid  glands  and 
make  them  open  on  the  exterior  of  the  cheek.*  By  attaching 
receptacles  to  the  orifices  of  these  displaced  ducts,  it  is  possible 
to  collect  separately  the  saliva  of  each  gland  and  to  study  its 
modifications  with  variations  in  the  food.  By  such  means  it 
has  been  found  by  Pawlow  that,  on  administration  of  meat  to 
a  dog,  the  saliva  which  is  secreted  is  derived  mainly  from  the 
submaxillary  gland  and  is  thick  and  viscid,  containing  a 
relatively  large  amount  of  mucin.  If,  on  the  other  hand,  dry 
powdered  biscuit  be  introduced,  the  resulting  secretion  is  thin 
and  watery,  and  is  obtained  from  both  sets  of  glands.  The 
introduction  of  stones  into  the  animal's  mouth  evokes  no 
secretion  at  all.  The  animal  can  get  rid  of  the  stones  by 
movements  of  the  tongue  without  any  preliminary  moistening. 
The  introduction  of  sand  into  the  animal's  mouth  is,  however, 
followed  by  a  copious  secretion  of  a  thin  watery  saliva,  which 
serves  the  purpose  of  washing  the  sand  from  the  surface  of 
the  mouth  and  enabling  this  substance  to  be  rejected  by  the 
animal.  These  facts  reveal  a  differential  activity  of  these 
glands  according  to  the  needs  of  the  animal.  Such  a  differen- 
tial secretion,  adapted  as  it  is  to  the  nature  of  the  substances 
present  in  the  mouth,  involves  the  intermediation  of  some 
complex  reactive  mechanism,  and  the  rapidity  with  which  the 
reaction  takes  place  indicates  that  we  must  seek  for  the 
mechanism  in  the  central  nervous  system — that,  in  fact,  we 


*  This  method,  which  has  been  iimch  employed  by  Pawlow,  was  first 
used  by  De  Graaf,  as  will  be  seen  from  the  figure  on  p.  81. 


44  THE    PHYSIOLOGY    OF    DIGESTION. 

have  here  a  complex  reflex  arc.  The  nervous  channels  of  the 
reflex  have  been  determmed  in  the  case  of  all  three  pairs  of 
salivary  glands.  The  afferent  channels  are  represented  by 
the  special  gustatory  nerves,  as  well  as  the  nerves  of  common 
sensation,  which  run  chiefly  in  the  fifth  and  ninth  cranial 
nerves  to  the  brain.  The  efl'erent  channels  vary  in  the  case 
of  the  different  glands.  Each  gland  receives  a  double  nerve 
supply,  viz.,  from  the  cranial  nerves  and  from  the  sympathetic 
system.  The  impulses  which  travel  along  the  sympathetic 
pass  out  from  the  spinal  cord  along  the  upper  two  or  three 
dorsal  nerve  roots ;  thence  they  travel  in  the  cervical  sympa- 
thetic to  the  superior  cervical  ganglia.  Here  there  is  a  new 
relay  of  fibres,  which  start  from  the  cells  of  the  ganglia  and 
travel  up  in  the  walls  of  the  branches  of  the  external  carotid 
artery  to  be  distributed  with  the  arteries  to  the  salivary 
glands.  The  cranial  supply  of  the  parotid  gland  arises  from 
the  ninth  nerve  and  passes  through  the  tympanic  plexus  into 
branches  of  the  fifth  nerve,  with  which  it  is  distributed  to  the 
gland.  The  fibres  to  the  submaxillary  and  sublingual  glands 
leave  the  brain  with  the  intermediate  nerve  of  Wrisburg  and 
pass  with  the  facial  into  the  chorda  tympani,  the  branches  of 
which  nerve  carry  the  impulses  to  the  gland.  The  centre 
must  be  located  somewhere  in  the  lower  part  of  the  cranial 
axis,  in  the  neighbourhood  of  the  pons  and  medulla. 

This  reflex  mechanism  can  be  set  into  activity,  not  only  by 
stimuli  applied  to  the  surface  of  the  mouth,  but  also,  in  default 
of  such  stimuli,  by  processes  which  must  be  located  in  the 
cortex  cerebri.  Pawlow  has  shown  that  the  specific  secretion  is 
evoked,  not  only  by  the  introduction  of  different  substances 
such  as  meat,  biscuit  powder,  or  sand  into  the  dog's  mouth, 
but  also  by  merely  showing  the  dog  the  substances  in  question, 
so  that  the  calling  up  of  the  psychical  images  of  these  sub- 
stances has  the  same  effect  as  their  actual  introduction  into 


SECRETION    OF    SALIVA.  45 

into  the  mouth.  As  soon  as  the  animal  reaHses  that  it  is 
being  played  with,  and  that  there  is  no  intention  of  really 
giving  it  these  things,  the  psychical  secretion  of  saliva  ceases. 

What  is  the  mechanism  of  this  secretion  ?  What  are  the 
changes  which  are  actually  responsible  in  each  gland  for  the 
production  of  a  secretion  ?  The  chief  experiments  bearing  on 
the  mechanism  of  secretion  have  been  made  upon  the  salivary 
gland,  since  this  forms  a  compact  organ,  which  can  be  easily 
isolated  from  other  tissues  without  injury  to  its  blood  and 
nerve  supply.  Moreover,  a  state  of  activity  is  readily  induced 
in  the  gland,  either  by  the  injection  of  drugs  such  as  pilocarpin, 
or  by  excitation  of  its  nerves,  w^hich  are  easily  accessible.  In 
investigating  th6  action  of  its  nerves  upon  the  gland,  a  small 
tube  or  cannula  is  placed  in  the  duct,  so  that  the  saliva  can  be 
led  off  and  measured  and  its  qualities  determined.  At  the 
same  time  the  chorda  tympani  and  the  sympathetic  nerves 
are  dissected  out  and  prepared  so  that  they  can  be  stimulated 
electrically.  It  is  found  that  these  two  sets  of  fibres  differ 
in  their  results  on  the  gland.  The  stimulation  of  the  peri- 
pheral end  of  the  chorda  is  at  once  followed  by  a  copious  flow 
of  thin  watery  saliva  which  contains  only  a  small  amount  of 
mucin.  There  is  also  great  dilatation  of  all  the  arterioles  of  the 
gland,  so  that  the  blood-flow  through  it  is  increased  five-  to 
eight-fold.  Stimulation  of  the  sympathetic  evokes  a  scanty 
secretion  of  thick  viscid  saliva,  generally  opalescent  in  appear- 
ance and  containing  a  relatively  large  amount  of  mucin.  On 
the  blood-vessels  the  action  of  the  sympathetic  is  the  reverse 
of  that  on  the  chorda.  The  sympathetic  carries  vaso-constrictor 
fibres  to  all  parts  of  the  head  and  neck.  The  arterioles  of  the 
gland  are  therefore  constricted,  and  the  flow  of  blood  through 
the  gland  very  largely  reduced. 

The  question  arises  whether,  in  these  two  sets  of  nerves, 
we  have  two  distinct  varieties  of  secretory  fibres  influencing 


46  THE    PHYSIOLOGY    OF    DIGESTION. 

different  parts  of  the  gland  cells,  or  whether  the  differences 
between  the  two  kinds  of  secretion  may  not  be  determined  by 
the  coincident  changes  in  the  blood  supply.  Heidenhain 
stated  that  the  histological  result -5  of  stimulating  the  sym- 
pathetic nerve  were  much  more  pronounced  than  those 
obtained  by  stimulating  the  chorda  tympani,  and  sug- 
gested that  the  nerves  to  the  glands  ought  to  be  divided 
into  two  classes,  namely  (1)  trophic  nerves,  e.g.,  sym- 
pathetic, which  influence  chiefly  the  metabolic  changes-  in 
the  cells  themselves,  and  (2)  secreto-motor  fibres,  which  deter- 
mine the  secretion  of  water  and  salt  by  the  glands.  Langley 
how^ever  has  been  unable  to  confirm  the  statement  of  Heidenhain 
as  to  the  peculiar  effects  of  the  sympathetic  on  the  structure 
of  the  glands.  According  to  Langley  the  histological  results 
of  stimulating  either  set  of  fibres  are  of  the  same  order.  On 
the  other  hand,  the  secretion  obtained  on  stimulating  the  chorda 
can  be  approximated  to  sympathetic  saliva  by  diminishing  the 
blood  flow  to  the  gland,  while  secretion  is  going  on,  either  by 
clamping  of  the  arteries  or  by  bleeding  the  animal.  Under 
these  conditions  the  saliva  becomes  thicker  and  more  viscid, 
and  its  percentage  of  solids  increases.  Langley  therefore  is 
inclined  to  regard  all  the  fibres  going  to  the  gland  as  of 
essentially  the  same  character,  namely  secretory;  and  considers 
the  differences  between  the  two  kinds  of  saliva  as  determined 
entirely  by  the  concurrent  vascular  changes  induced  by  stimu- 
lation of  the  two  sets  of  nerves.  It  has  been  urged  against  this 
view  of  the  identity  of  the  chorda  and  sympathetic  secretory 
fibres  that,  whereas  the  chorda  fibres  are  paralysed  by  a  minute 
dose  of  atropin,  it  is  very  difficult  to  affect  the  action  of  the 
sympathetic  even  by  large  doses  of  this  drug.  This  difference 
in  the  susceptibility  of  the  two  sets  of  fibres  to  the  action  of 
atropin  might  however  point  to  a  morphological  rather  than 
to  a  functional  distinction.     For  the  present,  therefore,  we  may 


SECRETION    OF    SALIVA.  47 

regard  the  glands  as  supplied  l)y  one  kind  of  fibre,  namely 
secretory,  in  addition  to  the  fibres  which  exercise  their  main 
influence  on  the  blood-vessels  of  the  gland  ;  and  we  may  treat 
the  effects  of  stimulation  of  the  chorda  tympani  as  typical  of 
the  state  of  activity  of  the  gland. 

On  investigating  the  conditions  of  secretion,  it  very  soon 
becomes  manifest  that  this  process  cannot  be  determined  by 
the  blood  pressure  within  the  blood  capillaries  of  the  gland,  how- 
ever much  the  changes  in  the  blood  supply  may  modify  the 
character  of  the  secretion.  Saliva  cannot  be  regarded  as  a 
simple  filtrate  from  the  blood  circulating  through  the  glands. 
This  is  shown,  in  the  first  place,  by  the  specific  composition  of 
the  saliva.  Although  amylase,  albumin,  and  globulin,  as  well 
as  salts,  are  present  in  the  surrounding  plasma,  this  fluid 
contains  no  trace  of  mucin.  Moreover,  though  it  is  possible, 
under  a  pressure  comparable  to  that  in  the  blood  capillaries, 
to  separate  by  filtration  from  the  blood  plasma  a  fluid  con- 
taining only  the  w^ater  and  salts  of  the  plasma,  it  would  be 
impossible  to  separate  off  a  salt  solution  of  the  composition  of 
saliva  without  the  application  of  a  force  far  transcending  in 
extent  even  the  arterial  blood  pressure.  Whereas  blood 
plasma  contains  a  mixture  of  salts  in  such  proportions  as  to 
be  isotonic  with  a  '9  per  cent,  solution  of  sodium  chloride, 
the  concentration  of  salts  in  the  saliva  is  only  equivalent  to 
about  '45  .per  cent,  sodium  chloride,  or  even  less,  i.e.,  the 
molecular  concentration  of  the  saliva  is  only  about  half  that 
of  the  blood  plasma.  Even  supposing  that  we  could  conceive 
of  a  filter  capable  of  keeping  back  one-half  the  salts  of  the 
blood  plasma,  it  would  require  a  pressure  of  several  atmo- 
spheres in  order  to  effect  the  separation  and  to  force  any  fluid 
at  all  through  the  filter.  The  osmotic  pressure  of  the  blood 
plasma  is  about  4,500  mm.  Hg.  The  osmotic  pressure  of  the 
saliva  would  be  less  than  3,000  mm.  Hg.,  so  that  a  minimum 


48  THE    PHYSIOLOGY    OF    DIGESTION. 

pressure  of  1,500  mm,  Hg.,  i.e.,  two  atmospheres,  would  be 
necessary  to  effect  the  separation  of  a  fluid  from  blood  plasma 
having  the  molecular  concentration  of  saliva. 

The  impossibility  of  explaining  the  process  of  secretion  as 
in  any  way  determined  by  the  blood  pressure  was  pointed  out 
long  ago  by  Carl  Ludwig.  Ludwig  showed  that,  if  a  mercurial 
manometer  be  connected  with  the  carotid  artery  of  an  animal, 
and  another  with  a  cannula  placed  in  the  duct  of  the  sub- 
maxillary gland,  the  occurrence  of  secretion  on  stimulation  of 
the  chorda  causes  the  manometer  attached  to  the  duct  to  rise 
to  a  height  much  greater  than  that  of  the  manometer  con- 
nected with  the  carotid  artery.  While  the  blood  pressure 
in  the  arteries  going  to  the  gland  may  be  120  mm.  Hg.,  the 
pressure  in  the  salivary  duct  may  rise  to  210  mm.  Hg.  This 
experiment  proves  conclusively  that,  somewhere  between 
blood-vessels  and  duct,  there  must  be  living  cells  which  are 
themselves  taking  an  active  part  in  the  process  of  secretion, 
and  furnishing  energy  for  the  process — energy  which  can 
be  derived  only  from  the  metabolism  of  the  cells,  and 
ultimately  from  the  oxidation  of  their  food- stuffs. 

Between  the  blood  and  the  duct  there  are  two  layers  of  cells, 
namely  the  delicate  endothelial  cells  forming  the  capillary 
wall,  and  the  much  larger  cells  which  form  a  continuous 
lining  to  the  ultimate  ramifications  of  the  gland-ducts,  the 
alveoli.  It  has  often  been  suggested  that,  in  the  process  of 
secretion,  the  endothelial  cells  and  vessels  must  take  an 
important  part,  and  this  view  was  not  directly  negatived  by 
the  action  of  atropin.  Atropin,  as  is  well  known,  prevents 
altogether  the  action  of  the  chorda  tympani  upon  secretion, 
i.e.,  it  paralyses  the  secretory  fibres  of  the  chorda  tympani. 
It  has  no  action,  however,  upon  the  vaso-dilator  fibres  of  this 
nerve,  so  that  stimulation  of  the  chorda  after  administration 
of  atropin  evokes  an  increased  flow  of  blood  through  the  gland 


SECRETION    OF    SALIVA.  49 

without  any  corresponding  secretion.     The  absence  of  secretion 
might  be  ascribed  equally  well  to  an  action  upon  the  endothe- 
lial cells  of  the  vessels  as  to  an  action  upon  the  cells  of  the 
secreting  alveoli.     To  decide  this  point  Gianuzzi  attempted  to 
paralyse  the  secretory  cells  by  the  injection  of  acid  into  the 
duct.     On  then  stimulating  the  chorda  tympani  no  secretion 
was  obtained,  but  the  gland  swelled  up  and  became  cedematous. 
This  observer  concluded  that  the  effect  of  the  injection  of  the 
acid  was  to  paralyse  the  secretory  cells  of  the  gland,  without 
paralysing  the  process  of  secretion  as  effected  by  the  endo- 
thelial  cells    and   blood-vessels.      This   explanation  is,  how- 
ever, incorrect.     The  injection  of  acid  injures,  not  only  the 
cells  of  the  alveoli,  but  also  the  endothelial  cells  of  the  blood- 
vessels, and,  as  in  any  other  injury,  the  production  of  vaso- 
dilatation causes  a  copious  transudation  of  lymph  through  the 
injured  vessel  wall,  and  therefore  the  production  of  oedema. 
A  consideration  of  the  other  changes  occurring  in  the  gland 
coincidently  with  secretion  shows  conclusively  that  the  active 
cells  are  not  the  vascular  endothelium,  but  the  cells  lining  the 
alveoli  themselves.     In  the  process  of  secretion  there  is  an 
evolution  of  energy.     We  have  to  determine  the  seat  and 
conditions   of  production   of   this   energy.      In   order   to   do 
this,  we  must  examine  more  carefallj^  the  various  changes 
which  occur  in  the  gland  concurrently  with   the  process  of 
secretion. 

1.  Blood-flow  through  the  Gland. — We  have  already  seen 
that  stimulation  of  the  chorda  tympani  nerve  causes  active 
vaso-dilatation  in  the  vessels  of  the  gland,  and  a  largely 
increased  flow  of  blood  through  this  organ.  The  same 
quickening  of  the  blood- flow  is  observed  when  the  gland  is 
excited  to  secrete  reflexly,  by  the  application  of  stimuli  to  the 
mucous  membrane  of  the  mouth,  or  by  the  injection  of  drugs 
such  as  pilocarpi!!.     During  active  secretion  the  blood-flow 

P.D.  E 


50  THE    PHYSIOLOGY    OF    DIGESTION. 

through  the  vessels  of  the  gland  is  increased  on  the  average 
to  five  times  the  amount  which  obtains  during  rest. 

As  a  result  of  stimulation  a  very  large  amount  of  water  is 

turned  out  through  the  gland  ducts.     In  one  experiment  of 

Heidenhain's*   220   cc.  of   saliva  were  secreted   by  a  gland 

weighing  about  6  grammes.     This  water  cannot  come  from 

the  gland  itself,  and  must  therefore  be  furnished  ultimately 

by  the  blood  which  circulates  through  the  vessels  of  the  gland. 

The  loss  of  water  by  the  blood  in  passing  through  the  gland 

has  been  determined  by  Barcroft,t  who  estimated  the  amount 

of  haemoglobin  in  the  arterial  blood  and  in  the  blood  which 

had  flowed   through  the  gland,  taking  into  account  at  the 

same  time   the  variations  in  the  rate  of   flow  through  the 

gland.     In  this  way  it  is  possible  to  compare  the  quantity 

of  fluid,  which  has  been  turned  out  by  the  gland  as  saliva, 

with   that  which  has  been  taken  up  by  the  gland  from  the 

blood.     The  amount  of  water  which  leaves  the  blood  may  be 

considerable,  so  that  the  blood  may  be  concentrated  by  as 

much   as   25  per  cent.,  and   Barcroft   has    shown   that   the 

volume  of  water  leaving  the  blood  is  always  somewhat  greater 

than  that  of   the  saliva  secreted.     Thus  in  one  experiment 

the  water  lost  by  the  blood  during  seven  minutes  amounted  to 

3*88  cc,  while  the  saliva  secreted  during  the  same  period  was 

only  3*52  cc.     In  this  case  the  ratio  of  water  lost  by  the  blood 

to  the  water  in  the  saliva  was  as  1*12  to  1,  and  in  all  Barcroft's 

experiments  the  water  lost   by  the  blood  was  about  10  per 

cent,  greater  than  the  water  leaving  the  gland  in  the  saliva. 

The  question  arises  as  to  the  destination  of  this  excess  of 

water  which  leaves  the  blood-vessels.     It  does  not  remain  in 

the  gland.     If  a  gland  be  stimulated  for  some  time,  it  is  always 

found  to  diminish  in  size  and  in  weight.     In  two  experiments 

*  Hermcmn's  Handbook,  Vol.  V.  (1),  1883. 
t  Journ.  of  Physiol  Vol.  XXV.,  p.  479,  1900. 


SECRETION    OF    SALIVA.  51 

by  Heidenhain,  the  right  gland  was  extirpated  and  weighed, 
and  then  the  left  chorda  tympani  was  stimulated  for  several 
hours.  The  saliva  secreted  was  measured,  and  at  the  end  of 
the  experiment  the  left  gland  was  cut  out  and  weighed.  The 
results  of  these  two  experiments  were  as  follows : — 


Saliva. 

Eight  gland. 

Left  gland, 

75  CC. 

6-86  g. 

5-42  g. 

220  CC. 

6-36  g. 

5-91  g. 

In  each  case  there  was  a  considerable  loss  of  weight,  and  this 
loss  of  weight  affected  the  solids  of  the  gland  even  more 
than  its  fluid  constituents.  The  resting  glands  contained 
28*3  per  cent,  total  solids,  whereas  the  two  active  glands  gave 
only  21*3  per  cent.  It  is  evident  that  all  the  water  which 
leaves  the  blood  must  leave  the  gland,  and  the  destiny  of 
this  water  is  at  once  revealed  on  examination  of  the  lymph 
flowing  from  the  gland.  The  lymph  passes  out  by  the 
lymphatic  vessels  in  the  hilus  of  the  gland,  and  finally 
makes  its  way  into  the  cervical  lymphatic  trunk.  If  the  other 
vessels  passing  into  this  trunk  be  ligatured,  a  cannula  can  be 
placed  in  the  trunk  towards  the  head,  and  the  lymph-flow 
obtained  will  represent  the  lymph  from  the  submaxillary 
gland.  This  experiment  has  been  performed  by  Bainbridge, 
who  finds  that  the  amount  of  lymph,  which  is  practically 
negligible  in  the  resting  gland,  is  markedly  increased  when 
secretion  takes  place.  The  total  quantity  of  lymph  is  about 
one-tenth  of  the  volume  of  saliva  secreted  at  the  same  time, 
so  that,  together  with  the  saliva,  it  exactly  corresponds  to  the 
volume  of  water  lost  by  the  blood  in  passing  through  the 
gland  (Figs.  1  and  2). 

It  might  be  imagined  that  this  increased  flow  of  lymph 
during  secretion  was  in  favour  of  the  view  put  forward  by 
Gianuzzi,  i.e.,  that  the  first  factor  in  secretion  was  an 
alteration  of   the   endothelial  cells  of  the  blood-vessels  and 

E  2 


62 


THE    PHYSIOLOGY    OF    DIGESTION. 


an  increased  transudation.  That  this  explanation,  however, 
is  not  correct  is  shown  by  some  experiments  of  Bunch, 
carried  out  in  this  laboratory,  on  the  changes  in  volume  of 


•♦5 


Volume  .'f 

blond  emerging 
from  gland -—lO 

/ 

^•'' 

■---.. 

Waier 

ost  by 

^\  / 

\ 

/ 

/' 

bio 

od 

/  ,.- 

^v 

Sal.va 

■  Fig.  1.  —  Diagram  showing  :  (ct)  Total  blood  flow 
through  submaxillary  gland.  (6)  Total  amount  of 
water  transferred  from  blood  to  gland,  (c)  Total 
secretion  of  saliva  (Barcroft). 

the  gland  during  secretion.     In  these  experiments  the  whole 
submaxillary   gland   was   placed   in    a  plethysmograph,  and 


5      10      15    ^0     ^S     3 


Vouuvc  0*  Gland 


Fia.  2. — Comparison  of  changes  in  volume  of  submaxillary 
gland  with  the  outflow  of  saliva  produced  by  stimulation 
of  the  chorda  tympani  nerve  (Bunch). 


SECRETION    OF    SALIVA. 


53 


its  volume  recorded  by  connecting  the  plethysmograph  with 
a  piston  recorder  writing  on  a  blackened  surface.  When 
vasodilatation  occurs  in  any  organ,  the  volume  of  the  blood- 
vessels is  increased,  and  therefore  one  would  expect  that  the 
vasodilatation,  which  accompanies  activity  of  the  salivary 
gland,  would  occasion  an  increase  in  the  volume  of  the  gland. 
This  is  the  case  in  a  gland  in  which  the  chorda  tympani  nerve 


(Xf^^xUaJ^oMA!^, 


X,^Ku«Au-2.SiCi. 


Kmaa^ZL  , 


Fig.  3. — Tracing  of  volume  of  submaxillary  gland,  showing 
effect  of  stimulation  of  the  chorda  after  administration  of 
10  mg.  atropine.  The  blood  pressure  (lowest  line)  was 
unaltered  by  the  stimulation  (Bunch). 

is  stimulated,  after  paralysis  of  its  secretory  fibres  by  the 
administration  of  a  small  dose  of  atropine.  The  vasodilatation 
which  results  gives  an  increase  in  the  volume  of  the  gland 
and  a  rise  in  the  recording  lever  (Fig.  3.)  The  same 
increase  in  the  volume  of  vessels  must  be  present  when 
secretion  is  allowed  to  take  place ;  but  a  record  of  the  volume 
of  the  gland  during  normal  secretion  shows  that  the  first 
effect  is  a  diminution  and  not  an  increase,  as  is  shown  in 
Fig.  4.  If  the  duct  be  clamped  so  as  to  prevent  the  escape 
of  saliva,  stimulation  of  the  chorda  gives  merely  an  increase 


54 


THE    PHYSIOLOGY   OF    DIGESTION. 


in  volume  (Fig.  5).     The  diminution  in  volume  observed  when 
the  duct  is  free  shows — 

(1)  That  the  first  result  of  exciting  the  secretory  nerves  is 
an  emptying  out  of  the  contents  of  the  gland; 

(2)  That  this  discharge  of  the  contents  of  the  gland,  as 
saliva,  is  more  than  sufficient  to  counterbalance  the  swelling 
of  the  gland,  produced  by  the  dilatation  of  its  blood-vessels. 


Fig.  4. — Tracing  of  volume  of  submaxillary  gland  showing 
decrease  on  excitation  of  chorda.  The  duct  was  free 
(Bunch). 


A  primary  increased  transudation  of  lymph  would  cause  an 
initial  expansion  in  the  volume  of  the  gland,  and  we  must 
conclude,  therefore,  that  the  first  effect  of  stimulation  is  not 
on  the  blood-vessels,  but  on  the  secreting  cells  of  the  alveoli, 
causing  them  to  empty  out  their  contents,  including  solids 
and  water.  Only  later  can  the  cells  recoup  themselves  at 
the  expense  of  an  increased  transudation  from  the  blood- 
vessels. 

This  loss  of  gland  substance  is  indicated  by  the  figures  I 


SECRETION    OF    SALIVA.  55 

have  quoted  above  on  the  changes  in  the  weight  and  in  the 
percentage  of  solids  of  the  gland  during  secretion.  The  same 
conclusion  is  borne  out  by  Pawlow's  estimations  of  the  amount 
of  nitrogen  in  secreting  and  resting  glands  respectively.  This 
observer  found  that,  whereas  ten  resting  glands  contained 
2' 18  gr.  of  nitrogen,  ten  glands  from  the  same  animals,  which 
had  been  stimulated  for  some  hours,  contained  only  1*872  gr. 
of    nitrogen,    representing    a    loss   by   these   glands   during 


Fig.  5. — Tracing  of  volume  of  submaxillary  gland,  showing 
effect  of  chorda  stimulation  after  obstruction  of  the  duct. 
It  will  be  noticed  the  volume  diminished  as  soon  as  the 
duct  was  released,  so  as  to  allow  the  saliva  to  flow  awav. 


secretion  of  '308  gr.  of  nitrogen.  The  saliva  obtained 
during  these  experiments  jdelded  '416  gr.  of  nitrogen,  so 
that  the  glands  had  taken  up  only  '19  gr.  of  nitrogen  {i.e., 
^j  of  the  total  amount)  from  the  blood  passing  through  them. 
Thus  the  primary  result  of  stimulating  the  secretory  nerves  is  to 
cause  the  gland  cells  to  discharge  their  organic  matter  together 
with  water  and  salts.  The  cells  then  recoup  themselves  at 
the  expense  of  the  blood  circulating  through  the  blood-vessels ; 
but  this  process,  although  practically  complete  in  the  case  of 


56  THE    PHYSIOLOGY    OF    DIGESTION. 

the  water  and  salts,  is  very  inadequate  in  the  case  of  the 
nitrogenous  constituents  of  the  cells,  which  have  been  lost  in 
the  saliva.  It  is  on  this  account  that  the  phenomena  of 
exhaustion  occur  on  prolonged  secretion. 

A  study  of  the  histological  changes  occurring  in  the  cells 
of  the  alveoli  during  secretion  points  to  the  same  conclusions. 
If  the  salivary  glands,  whether  parotid  or  submaxillary,  serous 
or  mucous,  be  teazed  with  salt  solution  or  serum  and  examined 
under  the  microscope,  the  appearances  observed  will  differ 
according  to  the  state  of  activity  of  the  gland  from  which  the 
specimens  have  been  made.  If  obtained  from  a  resting  gland, 
the  cells  are  swollen  and  packed  full  of  granules,  coarse  in  the 
case  of  the  mucous  glands,  fine  in  the  case  of  the  serous  glands. 
The  unaltered  protoplasm  of  the  cell  is  small  in  amount  and 
situated  chiefly  at  the  periphery,  away  from  the  lumen  of  the 
alveolus.  The  nucleus,  if  brought  into  view  by  the  addition 
of  reagents,  is  embedded  in  the  peripheral  zone  or  is  crushed 
against  the  basement  membrane,  and  becomes  easily  shrivelled 
under  the  action  of  hardening  reagents.  If,  however,  the 
cells  examined  be  taken  from  a  gland  which  has  been  secreting 
for  some  hours,  they  present  a  totally  different  appearance. 
The  cells  are  now  considerably  smaller  in  size ;  the  granules 
are  reduced  in  number,  and  are  confined  to  the  part  of  the 
cell  immediately  abutting  on  the  lumen.  The  protoplasm  has 
increased  in  amount  both  relatively  and  absolutely,  and  the 
nucleus  is  swollen  and  occupies  a  more  central  position  in  the 
cell.     Histologically,  then,  secretion  consists  in — 

(1)  A  discharge  of  the  granules. 

(2)  A  growth  of  protoplasm  ;  and 

(3)  Changes  in  the  appearance  of  the  nucleus. 

During  rest  we  must  assume  the  occurrence  of  reverse 
changes,  namely,  a  gradual  conversion  of  the  protoplasm  into 
granules  and  the  accumulation  of  these  granules  in  the  cell, 


SECRETION    OF    SALIVA.  57 

until  it  is  distended  with  them  and  swollen.  The  granules 
must  therefore  he  taken  as  representing  the  precursor  of  the 
secretion.  In  them  occur  the  changes  which  lead  to  the 
taking  up  of  water  and  the  discharge  of  the  granules,  dissolved 
and  perhaps  changed  in  character,  into  the  lumen  of  the 
secreting  alveoli. 

"We  have  already  learnt  that  there  is  an  expenditure  of 
energy  in  the  act  of  secretion,  and  it  is  important  that  we 
should  he  ahle  to  arrive  at  some  idea  of  the  extent  of  these 
energy  changes.  The  energy  balance  of  the  whole  body  is 
most  easily  obtained  by  an  examination  either  of  the  total 
potential  energy  presented  to  the  body  in  the  shape  of  food, 
or  better  by  an  analysis  of  the  excreta  consisting  of  carbon 
dioxide,  water,  and  nitrogenous  end-products  such  as  urea. 
Nine-tenths  of  the  total  energy  set  free  in  the  body  by  the 
combustion  of  the  foodstuffs  is  represented  by  the  carbon 
dioxide  output  of  the  bod3^  We  can  therefore  probably 
arrive  at  a  fairly  true  idea  of  the  energy  changes  in  the  sub- 
maxillary gland  by  examining  its  intake  of  oxygen  and  its 
output  of  carbon  dioxide.  In  the  whole  body  these  two 
amounts  correspond,  though  there  is  always  a  small  loss  of 
oxygen,  about  one-fifth  of  the  w^hole,  which  is  required  for 
the  oxidation  of  substances  other  than  carbon  in  the  body. 
"When,  however,  we  are  dealing  with  an  isolated  organ,  the 
oxygen  intake  is  considerably  more  valuable  than  the  carbon 
dioxide  output.  There  is  no  evidence  that  the  body  in  any 
of  its  tissues  is  able  to  store  oxygen,*  so  that  the  intake 
of  oxygen  must  be  proportional  at  any  time  to  the  require- 
ments of  the  body.     On  the  other  hand,  all  the  alkaline  juices 


*  Many  physiologists  might  not  agree  with  this  statement.  All  would 
agree,  however,  that  the  power  of  living  tissues  to  store  oxygen  is 
extremely  limited. 


58  THE    PHYSIOLOGY    OF    DIGESTION. 

of  the  body  contain  carbonates  or  bicarbonates.  Any  change 
in  reaction  of  these  fluids  will  alter  their  power  of  taking  up 
carbon  dioxide,  and  the  mere  production  of  acid  may  therefore 
give  rise  to  an  evolution  of  CO2  which  has  not  been  imme- 
diately formed  by  the  cells.  On  the  other  hand,  increased 
alkalinity  of  the  juices  will  enable  these  to  take  up  more  CO2, 
and  prevent  therefore  the  output  of  carbon  dioxide  to  the 
blood  circulating  through  the  capillary  vessels. 

The  question  of  the  gaseous  exchanges  of  the  submaxillary 
gland  has  been  investigated  by  Barcroft.*  The  following  table 
represents  the  average  figures  obtained  from  a  number  of 
observations.  In  these  experiments  the  blood  gases  were 
estimated  in  the  arterial  blood  and  also  in  samples  of  blood 
obtained  from  the  veins  of  the  submaxillary  gland.  From  the 
difference  between  these  two  figures  it  was  possible  to  reckon 
the  amount  of  oxygen  taken  up  and  the  amount  of  carbon 
dioxide  discharged. 

Gaseous  Exchange  of  Submaxillaey  Gland  (Barcroft). 
O2  taken  up.  CO2  output. 

Besting  . .        '25  cc.  per  minute.      .  .        '17  cc.  per  minute. 

Active  , .       '86  cc.  ,,  . .        '39  cc.  ,, 

It  will  be  observed  that,  whereas  the  flow  of  blood  through 
the  gland  may  be  increased  five  or  six  times  during  activity, 
the  quantity  of  oxygen  taken  up  by  the  cells  is  increased 
about  three  and  a  half  times.  Although  the  total  loss  of 
oxygen  from  blood  to  gland  is  increased,  the  relative  loss  is 
diminished,  and  the  blood  flowing  from  the  veins  of  a  gland 
during  activity  is  more  arterial  in  colour  and  contains  more 
oxygen  than  the  blood  obtained  from  a  resting  gland.  If  we 
assume  that  the  total  oxygen  taken  up  is  employed  in  the 
oxidation  of  a  food  substance  such  as  glucose,  and  that  the 

-  Journ.  of  Physiol  Vol.  XXVII.,  p.  31,  1901. 


SECRETION    OF    SALIVA.  59 

whole  of  the  energy  of  the  chemical  changes  is  set  free  in  the 
form  of  heat,  we  find  that  a  resting  gland  weighing  about  6 
grammes  produces  about  1*1  calories  per  minute,  whereas  an 
active  gland  produces  about  3*8  calories  per  minute.  We 
know,  however,  that  a  certain  amount  of  external  work  is  per- 
formed in  the  secretion  of  a  saliva  containing  less  salts  than 
the  original  blood,  and  also,  when  there  is  any  resistance  to 
the  flow  of  saliva  through  the  duct,  in  raising  the  hydrostatic 
pressure  of  the  saliva  in  the  duct  to  a  height  greater  than  that 
in  the  blood  capillaries. 

Can  we  from  all  these  data  form  a  conception  of  the  total 
changes  occurring  in  the  gland  and  involved  in  the  formation 
of  the  secretion  ?  Even  during  rest,  changes  are  going  on  in 
the  gland  cells,  changes  which  involve  the  taking  up  of  food 
material  and  its  assimilation  under  the  influence  of  the 
nucleus,  perhaps  into  the  nucleus  itself,  and  certainly  into 
the  undifferentiated  cytoplasm.  In  this  cytoplasm  a  further 
change  occurs,  leading  to  its  transformation  into  granules. 
When  activity  is  excited  by  the  stimulation  of  secretory 
nerves,  the  primary  change  appears  to  involve  simply  the 
granules.  These  structures  must  absorb  water,  apparently 
against  osmotic  pressure.  Those  nearest  the  lumen  swell 
up,  become  converted  into  spheres  containing  water  and 
salts  in  smaller  proportion  than  exists  in  the  lymph  bathing 
the  cells  (and  presumably  in  the  protoplasm  surrounding 
the  granules),  and  in  this  swollen  form  are  discharged  or 
ruptured  on  the  periphery  of  the  cell  into  the  lumen,  so 
giving  rise  to  secretion.  This  discharge  of  a  fluid  with  a 
smaller  molecular  concentration  than  the  cell  or  surrounding 
blood  plasma  must  lead  to  an  increased  concentration  in 
the  remaining  parts  of  the  cell.  The  increased  concentration 
would  naturally  induce  a  flow  of  water  from  lymph  into 
cell,  and  the  consequent  concentration  of  the  lymph  would 


60  THE    PHYSIOLOGY    OF    DIGESTION. 

in  the  same  way  cause  a  flow  of  water  from  blood  to 
lymph.  This  pull  of  water  by  the  cell  from  the  blood  is 
still  further  increased  in  another  way.  The  act  of  secretion, 
involving  as  it  does  the  expenditure  of  energy,  can  be  carried 
out  only  at  the  expense  of  chemical  changes  in  the  cell. 
These  chemical  changes,  as  in  all  other  metabolic  processes 
of  the  body,  will  result  in  the  formation  of  a  number  of  small 
molecules  from  the  great  colloid  molecules  of  the  protoplasm 
with  its  side-chains.  The  products  of  metabolism,  or  meta- 
bolites, will  therefore  accumulate  in  the  cell,  pass  into  the 
lymph,  and  increase  the  concentration  of  the  latter.  The 
increased  concentration  will  call  forth  an  increased  transuda- 
tion of  fluid,  e.g.,  water,  from  the  blood  vessels,  and  the 
transudation  thus  evoked  will  be  greater  than  that  necessary 
to  provide  the  water  of  the  saliva,  and  will  therefore  produce 
a  distension  of  the  lymphatic  spaces  of  the  gland,  and  an 
increased  discharge  of  lymph  along  its  efferent  lymphatics. 
As  a  secondary  result  of  the  activity,  perhajDS  in  consequence 
of  the  removal  of  the  products  of  the  resting  metabolism  of 
the  gland,  there  is  increased  growth  of  protoplasm,  increased 
activity  of  the  nucleus,  and  therefore  a  tendency  to  increased 
assimilatory  changes  and  a  preparation  of  the  cell  for  further 
secretory  changes  either  immediately  or  hereafter. 

In  the  gland  however,  as  in  muscle,  when  we  attempt  to 
form  a  conception  of  the  mechanism  of  the  chemical  machine 
in  the  living  cell,  we  are  brought  up  against  insuperable 
difficulties.  One  might  perhaps  conceive  of  the  secretory 
granules  being  bounded  by  a  membrane,  impermeable  to  inter- 
mediate metabolites  and  salts,  but  permeable  to  carbon  dioxide. 
If  the  first  effect  of  stimulation  of  the  secretory  nerves  were  to 
produce  an  explosive  disintegration  of  the  complex  molecules 
making  up  the  granules,  we  should  have  a  sudden  multiplica- 
tion of  molecules  within  the  granules.     This  would  cause  a 


SECRETION    OF    SALIVA.  61 

large  rise  of  the  osmotic  pressure  in  these  granules  and  the 
consequent  absorption  of  water  from  the  surrounding  pro- 
toplasm. This  process  however  could  only  result  in  the 
production  of  a  fluid  in  the  granules,  having  the  same  osmotic 
pressure  as  the  surrounding  medium,  whereas  we  know  that 
saliva  has  a  molecular  concentration  which  is  only  one-half 
that  of  the  blood  or  lymph.  We  should  therefore  have  to 
make  a  second  assumption  ;  namely,  that,  before  the  extrusion 
of  the  solution  from  the  granules,  there  is  a  further  break- 
down of  the  metabolites  by  a  process  of  oxidation,  with  the 
production  of  carbon  dioxide  which  diffuses  into  the  sur- 
rounding protoplasm.  We  have  however  no  evidence  of 
either  of  these  processes  or  for  any  of  these  assumptions,  and 
I  have  only  adduced  them  in  order  to  show  how  far  we  are 
still  from  the  actual  comprehension  of  the  events  occurring  in 
every  living  cell,  and  determining  its  conditions  of  rest  and 
activity. 


LECTUEE    IV. 

DIGESTION    IN    THE    STOMACH. 

The  food,  which  has  been  masticated  in  the  mouth  and 
thoroughly  moistened  with  saliva,  is  swallowed  at  successive 
intervals,  and  collects  to  form  a  mass  lying  in  the  fundus  of 
the  stomach.  This  mass,  impregnated  with  saliva  and  kept 
at  the  body  temperature,  is  penetrated  only  with  difficulty  by 
any  juice  secreted  in  the  stomach,  so  that,  in  those  animals 
whose  saliva  contains  ptyalin,  the  process  of  salivary  digestion 
■can  go  on  unchecked,  at  any  rate  in  the  centre  of  the  mass, 
for  twenty  to  forty  minutes. 

Even  before  the  food  reaches  the  stomach,  a  special  digestive 
fluid,  the  gastric  juice,  is  poured  out  into  the  stomach.  This 
juice  is  strongly  acid  in  character.  As  it  penetrates  the  mass 
of  food,  the  acid  first  checks  the  action  of  the  ptyalin  and 
finally  destroys  it.  The  gastric  juice  is  the  product  of  secre- 
tion of  a  number  of  tubular  glands,  which  are  set  thickly 
over  the  whole  surface  of  the  stomach,  and  form  the 
greater  part  of  the  mucous  membrane.  On  examining  the 
internal  surface  of  the  stomach,  there  is  seen  to  be  a  difference 
between  the  appearance  of  the  mucous  membrane  over  the 
four-fifths  of  the  stomach  nearest  to  the  cardiac  end  and 
that  covering  the  fifth  immediately  adjoining  the  pyloric 
orifice.  In  the  latter  position  the  mucous  membrane  is 
somewhat  different  in  hue,  being  less  pink  than  the  fundus 
mucous  membrane,  and  presents  much  fewer  folds  owing  to 
its    closer    attachment    to    the    subjacent    muscular    tissues. 


DIGESTION    IN    THE    STOMACH.  '  63 

In  the  dead  stomach  there  is  no  external  sign  of  this  differ- 
ence between  the  mucous  membrane  at  the  two  ends  of  the 
stomach ;  but  in  the  Hving  stomach,  or  in  the  stomach  just 
removed  from  the  animal  and  kept  in  warm   salt  sokition, 
the  line  of  demarcation  between  the  two  types  of   mucous 
membrane   is   marked    externally   by   a   deep   furrow,    often 
spoken  of  as  the  'transverse  band.'     In  many  cases,  the  whole 
segment  of  the  stomach  between  this  transverse  band  and  the 
pyloric  orifice  is  contracted  to  form  a  tube,  which  looks  as 
if  it  were  a  direct  continuation   upwards   of   the   intestinal 
tube.     There  is  a  marked  difierence  between  the  movements 
carried    out   by   the   two    portions   of    the    stomach.       The 
cardiac  end  and  fundus  represent  a  sort  of  reservoir,  which 
is  distended  by,  and  slowly  contracts  upon,  the  mass  of  food, 
driving  all  its  fluid  portions  towards  the  pyloric  end.     In  the 
pyloric  fifth  of  the  stomach  there  is  a  continual  series  of  waves 
of  contraction,  which  pass  from  near  the  transverse  band  to  the 
pylorus  and  provide  for  a  thorough  admixture  of  the  fluid 
parts    of   the   food   with   the   secreted    gastric   juice,  finally 
expelling  the  semi-digested  chyme  through  the  pyloric  orifice 
into  the  duodenum.     Although  both  parts  of  the  stomach  are 
beset  with  tubular  glands,  there  are  important  differences  in 
.the  structure  of  the  glands  in  the  two  parts.     In  man  and  dog 
the  tubular  glands  in  the  fundus  present  a  neck  or  duct  which 
is  lined  with  simple  columnar  cells  and  forms  one-third  of  the 
whole   gland.      Into   this   duct   open   one   or   two   secreting 
tubules,  which    are    lined    by  epithelial  cells  of   two    kinds, 
namely,  the  central  or  peptic  cells,  and   large  oval  cells  lying 
between  them  and  the  basement  membrane,  the  parietal  or 
oxyntic  cells.     At  the  pyloric  end  the  ducts  form  from  one-half 
to  two-thirds  of   the  glands  and  divide   into  three  or   four 
secreting  tubules.     The  latter  present  only  one  kind  of  cell, 
which  is  similar  to  the  pejDtic  or  central  cell  in  the  fundus 


64  THE    PHYSIOLOGY    OF    DIGESTION. 

glands.  Since  it  has  been  found  that  the  secretion  of  the 
fundus  glands  contains  hydrochloric  acid  as  well  as  the  pro- 
teolytic ferment,  pepsin,  whereas  that  obtained  from  the 
pyloric  glands  contains  no  free  hydrochloric  acid,  but  only 
pepsin,  it  has  been  concluded  that  the  parietal  cells  secrete 
the  acid,  while  the  central  cells  in  both  types  of  gland 
secrete  the  pepsin.  The  changes  in  the  latter  cells,  which 
accompany  activity,  are  exactly  analogous  to  those  we  have 
already  studied  in  the  salivary  glands,  the  resting  cells 
being  loaded  with  granules  which  are  discharged  during 
activity. 

In  order  to  determine  the  characters  of  gastric  jaice,  we 
must  have  some  method  at  our  command  of  obtaining  it  in 
sufficient  quantity,  free  from  admixture  with  food  substances, 
or  other  secretions  such  as  saliva.  In  the  case  of  the  stomach 
we  cannot  connect  a  cannula  with  a  main  duct  and  so  lead 
away  the  secretion  obtained  during  a  meal.  We  must  there- 
fore take  the  secretion  which  is  poured  into  the  whole  cavity 
of  the  stomach,  and  adopt  some  method  which,  while  retaining 
the  normal  stimulus  of  a  meal,  will  prevent  the  entry  of  food 
into  the  stomach  or  into  that  portion  which  we  use  for  our 
experiment. 

It  is  comparatively  easy  in  dogs  to  establish  a  fistulous 
opening  into  the  stomach,  and  so  collect  any  juice  which  is 
poured  out  in  this  viscus.  In  such  animals  it  is  found  to  be 
impossible  to  evoke  secretion  into  the  stomach  by  mechanical 
excitation  of  its  internal  surface,  whereas  it  is  only  necessary 
to  show  the  dog  food,  or  allow  it  to  begin  the  mastication  of 
food,  in  order  to  produce  a  flow  of  gastric  juice.  In  order  to 
collect  the  juice  poured  out  under  such  circumstances,  free 
from  admixture  with  food  or  saliva,  Pawlow  has  adopted  the 
method  of  dividing  the  oesophagus  in  the  neck  and  bringing 
the  two  ends  to  the  surface.     At  the  same  time  a  fistulous 


DIGESTION    IN    THE    STOMACH. 


65 


opening  is  established  through  the  abdominal  wall  into  the 
stomach.  Such  animals  can  be  fed  by  the  introduction  of 
fluid  food  through  the  lower  cut  end  of  the  oesophagus,  or 
directly  through  the  fistulous  opening  into  the  stomach. 
They  can  also  take  a  meal  in  the  ordinary  way,  but  the  food 
which  is  swallowed  will  always  fall  out  of  the  opening  of  the 


Fig.  6. — Diagram  showing  the  manner  in  which  the  stomach  is  divided 
into  two  cavities,  separated  only  by  a  diaphragm  of  mucoas  membrane, 
and  still  in  muscular  and  nervous  continuity.  V.  Cavity  of  main 
stomach.  S.  Small  or  sample  stomach  opening  on  to  exterior. 
A.- A.  Abdominal  wall. 

oesophagus  on  the  surface  of  the  neck,  none  of  it  reaching  the 
stomach.  Pawlow  has  shown  that  if  such  an  animal  be 
given  food,  when  hungry,  it  will  eat  with  avidity,  and  since 
the  food  cannot  reach  the  stomach  and  so  satisfy  its  hunger, 
it  will  continue  to  eat  for  two  or  three  hours.  Five  minutes 
after  the  beginning  of  this  sham  feeding,  gastric  juice  begins 
to  drop  from  the  fistulous  opening;    and  in  this  way  large 

P.D,  F 


66  THE    PHYSIOLOGY    OF    DIGESTION. 

quantities   of    juice,   free    from    any   admixture   with   other 
substances,  can  be  easily  obtained. 

By  this  means  we  obtain  a  secretion  of  gastric  juice,  which 
is  excited  by  the  presence  of  food  in  the  mouth.  This  method 
does  not,  however,  enable  us  to  determine  whether  the 
character  of  the  juice  will  be  altered  in  any  way  by  the 
changes  w^hich  the  food  undergoes  in  the  stomach  itself. 
In  order  to  form  an  idea  of  the  normal  course  of  secretion 
of  gastric  juice,  when  food  is  taken  into  the  stomach  in  the 
ordinary  way,  Pawlow  has  devised  another  procedure.  A 
small  diverticulum  representing  about  -^q  of  the  whole  stomach 
is  made  at  the  cardiac  or  pyloric  end,  in  direct  muscular 
and  nervous  continuity  with  the  rest  of  the  stomach,  but 
shut  off  from  the  main  part  of  the  viscus  by  a  diaphragm  of 
mucous  membrane.  The  method  in  which  this  operation  is 
carried  out  will  be  evident  by  reference  to  the  diagram  (Fig.  6). 
In  a  dog  treated  in  this  w^ay  it  is  found  that  the  amount  of  juice 
secreted  by  the  small  stomach  always  bears  the  same  ratio  to 
the  amount  secreted  by  the  large  stomach,  w^hile  the  digestive 
power  of  the  juice  obtained  from  the  small  stomach  is  equal 
to  that  obtained  from  the  large.  This  is  shown  in  the  following 
table.* 

In  this  case  a  fistulous  opening  had  been  established  into  the 
large  stomach,  so  that  the  juice  could  be  obtained  simul- 
taneously from  both  sections  of  this  organ.  Secretion  was 
excited  by  a  sham  meal,  in  which  the  food  taken  by  the 
animal  dropped  out  of  an  opening  in  the  neck,  and  was  not 
allow^ed  to  reach  the  stomach.  It  will  be  seen  that  the 
secretions  in  the  two  sections  of  the  stomach  run  parallel  to 
one   another,   while    there   is    an   almost   exact   equivalence 


*  Pawlow,  "  The  Work  of  the  Digestive  Glands  "  (translated  by  W.  H. 
Thompson,  M.D.),  p.  80. 


DIGESTION    IN    THE    STOMACH. 


67 


between  the  strengths  of  the  juicesobtamedfrom  each  section. 
We  may  therefore  regard  the  secretion  obtained  from  the 
small  stomach  as  a  sample  of  that  produced  by  the  large,  and 
from  the  changes  in  this  small  stomach  judge  of  the  effects 
occurring  in  the  whole  organ.  By  this  method  it  is  possible 
to  study  the  effects  of  a  normal  meal  in  which  the  food  is 
swallowed,  or  of  a  sham  meal  in  which  the  food  is  merely 
masticated  in  the  mouth,  or  of  a  meal  in  which  the  food  is 
directly  introduced  into  an  opening  into  the  large  stomach. 


Secretion  from  Gastric  Fistul.^  after  Sham  Meal. 


Small  Stomach. 

Large  Stomach. 

Hours. 

Quantity. 

Strength.* 

Quantity. 

Strength. 

1  ..       .. 

2  ..      .. 

3  ..      .. 

7-6  CO. 
4-7  cc. 
1-1  cc. 

5-88  mm. 
5 "75  mm. 
5*5    mm. 

68-25  cc. 
41-5    cc. 
140    cc. 

5-5    mm. 
5*5    mm. 

5-38  mm. 

Total   .  . 

13-4  cc. 

— 

123-75  cc. 

— 

The  gastric  juice  obtained  in  any  one  of  these  ways  is  a  clear 
colourless  fluid  like  water,  containing  from  0*3  to  1  per  cent, 
total  solids,  and  having  an  acidity  equivalent  to  0*48  per  cent, 
hydrochloric  acid.  If  obtained  from  the  fundus,  and  there- 
fore acid  in  reaction,  it  has  a  strong  digestive  action  on 
proteids.  If  allowed  to  act  on  proteids  for  prolonged  periods, 
it  converts  a  large  proportion  of  these  bodies  into  amino - 
acids    and   other   products.      In   the    course   of    a    digestion 


*  The  strength  of  the  juice  was  determined  by  measm^ing  the  number 
of  milhrnetres  of  coagulated  egg  white  (in  Mett's  tubes)  which  were 
digested  in  eight  hours. 

F    2 


68  THE    PHYSIOLOGY    OF    DIGESTION. 

extending  over  three  to  six  hours,  i.e.,  the  time  usually 
occupied  by  gastric  digestion,  the  greater  part  of  the  proteid 
is  converted  only  into  its  first  products  of  hydration,  namely, 
albumoses  and  peptones,  and  it  is  in  this  condition  that 
the  proteids  of  the  food  are  normally  passed  on  into  the 
first  section  of  the  small  gut.  This  action  of  the  gastric 
juice  on  proteids  must  be  ascribed  to  the  presence  in  the  juice 
of  a  ferment,  pepsin,  acting  in  conjunction  with  free  hydro- 
chloric acid.  If  the  collected  juice  be  placed  in  an  ice  chest 
for  twenty-four  hours,  it  will  become  turbid  from  the  produc- 
tion of  a  finely  granular  precipitate.  The  precipitate  gradually 
sinks  to  the  bottom,  and  probably  represents  pepsin  in  the 
purest  form  in  which  it  is  possible  to  obtain  it.  That  pepsin 
forms  an  unstable  compound  with  the  hydrochloric  acid  is 
shown  by  the  fact  that,  if  two  portions  of  the  cooled  fluid  be 
taken,  one  from  the  clear  layer  near  the  top  of  the  vessel  and 
the  other  from  the  turbid  suspension  at  the  bottom,  the  latter, 
which  contains  the  greater  part  of  the  pepsin,  contains 
also  a  larger  percentage  of  hydrochloric  acid  than  the  top 
layer.  If  the  hydrochloric  acid  were  absolutely  free  in  the 
solution,  its  distribution  throughout  the  fluid  would  be  the 
same. 

We  must  now  inquire  into  the  conditions  which  determine 
the  secretion  of  the  gastric  juice.  The  method,  which  we 
must  adopt  for  its  collection,  shows  that  we  have  here  to  do, 
in  the  first  place,  with  a  reflex  nervous  mechanism,  since  an 
active  secretion  is  excited  by  the  presence  of  food  in  the 
mouth  and  by  its  mastication.  Moreover,  a  secretion,  which 
is  at  least  as  vigorous  as  that  produced  by  a  sham  meal, 
can  be  evoked  by  merely  arousing  in  the  dog  the  idea  of  a 
meal.  In  this  case  the  secretion  must  be  determined  by 
events  in  the  brain  which  involve  the  co-operation  of  the 
cerebral  cortex.     If  the  animal  be  hungry,  it  is  sufficient  to 


DIGESTION    IN    THE    STOMACH. 


69 


show  it  the  food  to  produce  a  secretion.  In  the  experiment 
from  which  the  following  table  is  taken,  the  dog  was  continually 
excited  by  showing  it  meat  during  a  period  of  an  hour  and  a 
half.  At  the  end  of  this  time  the  animal,  which  had  an 
oesophageal  fistula,  was  given  a  sham  meal.  It  will  be 
observed  that  the  psychical  secretion  obtained  during  the 
first  period  of  the  experiment  was  rather  greater  than  the 
secretion  produced  by  the  introduction  of  food  into  the  mouth. 


Psychical  Secretion  of  Gastric  Juice. 

(Pawlow.) 

Time. 

Quantity. 

8  minutes 

10  CO. 

4 

10  „ 

4 

10  „ 

10 

10  „ 

10 

10  „ 

8 

10  „ 

8 

10  „ 

19 

10  „ 

19 

8  „ 

Sham  Feeding. 

Time. 

Quantity. 

17  minutes 

10  cc. 

9        „ 

10  ,, 

8        „ 

10  „ 

The  afferent  channels  for  this  reflex  may  be  therefore  either 
the  afferent  nerves  from  the  mouth,  or,  when  the  idea  of  food 
is  involved,  any  of  the  nerves  of  special  sense,  such  as  sight, 
smell,  or  hearing,  through  which  these  ideas  are  called  forth. 
The  efferent  channels  can  only  be  one  of  two  nerves,  viz  : — the 
vagus  and  the  sympathetic,  since  these  are  the  only  two  which 
are  distributed  to  the  stomach.  That  it  is  the  former  of  these 
nerves  which  is  involved  is  shown  by  the  fact,  recorded  by 
Pawlow,  that  psychical  secretion,  as  well  as  the  results  of  a 
sham  meal,  are  entirely  abolished  by  division  of  botli  vagi. 
On  this  account  division  of  both  vagi  may  give  rise  to  entire 


70  THE    PHYSIOLOGY    OF    DIGESTION. 

absence  of  gastric  digestion,  and  death  of  the  animal  may 
ensue  from  inanition,  or  from  ]Doisoning  by  the  products  of 
decomposition  of  food  in  the  stomach,  even  when  care  has 
been  taken  to  avoid  injury  to  the  pulmonary  and  tracheal 
branches  of  these  nerves. 

The  converse  experiment  of  exciting  secretion  by  direct 
stimulation  of  the  vagus  presents  greater  difficulties.  Stimu- 
lation of  the  vagus  in  the  neck  causes  stoppage  of  the  heart, 
and  consequent  ansemia  of  the  mucous  membrane  of  the 
stomach.  Moreover,  the  stomach  seems  to  be  much  more 
susceptible  than  the  salivary  glands  to  the  action  of  poisons, 
such  as  anaesthetics.  Its  activity  is  also  easily  affected  by 
inhibitory  impulses  arising  in  the  central  nervous  system 
as  the  result  of  either  painful  impressions  or  emotional  states 
of  the  animal.  In  order  to  avoid  these  disturbing  factors 
Pawlow  proceeded  as  follows  : — An  animal  with  fistulae  of 
oesophagus  and  stomach  had  one  vagus  nerve  divided.  A 
thread  was  attached  to  the  peripheral  end  of  the  cut  vagus 
and  allowed  to  hang  out  through  the  wound.  Four  days  after 
the  operation  the  vagus  was  drawn  out  of  the  wound  by  care- 
fully pulling  on  the  thread,  so  as  not  to  hurt  or  frighten  the 
animal  in  any  way,  and  its  peripheral  end  stimulated  by 
means  of  induction  shocks.  No  effect  was  produced  on  the 
heart,  owing  to  the  degeneration  of  the  cardio-inhibitory  fibres, 
which  is  well  known  to  occur  within  this  period  after  section. 
Five  minutes  after  the  commencenaent  of  the  stimulation,  the 
first  drop  of  gastric  juice  appeared  from  the  gastric  cannula, 
and  a  steady  secretion  of  juice  was  obtained  with  continuation 
of  the  stimulation.  This  experiment  furnishes  the  decisive 
and  final  evidence  that  the  secretory  nerves  to  the  stomach  run 
in  the  two  vagi.  There  is  one  marked  difference,  however, 
between  the  action  of  these  nerves  and  the  action  of  the 
chorda  tympani   nerve  on  the    submaxillary  gland,  namely. 


DIGESTION    IN    THE    STOMACH.  71 

the  great  length  of  the  latent  period  before  gastric  secretion 
occurs.  The  length  of  this  latent  period  has  not  yet 
been  satisfactorily  explained.  It  cannot  be  due  to  delay 
occurring  between  the  vagus  fibres  and  the  local  nervous 
mechanism  in  the  stomach.  It  may  be  that  the  chemical 
changes  finally  resulting  in  secretion  require  a  longer  period 
for  their  accomplishment  than  is  the  case  in  the  salivary 
gland.  Physiologically  there  is,  indeed,  no  special  need  for  a 
rapid  secretion  of  gastric  juice,  whereas  in  the  mouth  it  is 
essential  that  the  introduction  of  food  should  be  immediately 
followed  by  the  production  of  saliva,  for  the  tasting  and 
testing  of  the  food  and  for  its  subsequent  mastication  or 
rejection.  Another  possible  explanation  of  this  prolonged 
latent  period  we  shall  have  to  consider  later. 

These  experiments  show  conclusively  that  an  important — 
probably  the  most  important — part  of  the  gastric  secretion  is 
determined  by  a  nervous  mechanism.  This  nervous  secretion 
does  not,  however,  account  for  the  whole  of  the  gastric  juice 
obtained  as  the  result  of  a  meal.  If  an  animal  provided  with  two 
gastric  fistulse,  one  into  a  diverticulum  and  the  other  into  the 
main  stomach,  have  both  its  vagi  divided,  it  is  found  that  the 
introduction  of  meat  into  the  large  stomach  is  followed,  after 
a  period  of  twenty  to  forty-five  minutes,  by  the  appearance  of 
a  secretion  of  gastric  juice  from  the  small  stomach.  More- 
over, when  an  animal  is  given  a  normal  meal,  and  is  allowed 
to  swallow  the  food  after  mastication,  the  total  amount  of 
gastric  juice  obtained  is  greater  than  that  produced  by  the 
sham  feeding  alone,  and  the  flow  is  of  longer  duration.  In 
fact,  we  may  say  that  the  gastric  juice  secreted  in  response 
to  a  normal  meal  consists  of  two  parts,  viz.,  (1)  a  large  amount, 
the  secretion  of  which  begins  within  five  minutes  of  the  taking 
of  the  food  and  is  determined  by  the  reflex  nervous  mechanism 
described  above;  and  (2)  a  smaller  portion,  the  secretion  of 


72 


THE    PHYSIOLOGY    OF    DIGESTION. 


which  is  excited  by  the  presence  of  the  food  in  the  stomach. 
This  combmed  character  of  the  gastric  juice  produced  by  a 
normal  meal  is  shown  in  the  following  table  :* 


Secretion  of  Gastric  Juice. 


Hours. 

Normal  meal. 

200  gr.  meat  into 

stomach. 

150  gr.  meat  into 
stomach. 

Sham  meal. 

Sum  of  two 

last  ex- 
periments. 

Quantity, 
cc. 

Strength, 
mm.  dig. 

Quantity, 
cc. 

Strength, 
mm.  dig. 

Quantity, 
cc. 

Strength, 
mm.  dig. 

Quantity, 
cc. 

1  .. 

2  .. 

3  .. 

4  .. 

12-4 

13-5 

7-5 

4-2 

5-43 
3-63 
3-5 
3-12 

5-0 
7-8 
6-4 
5-0 

2-5 
2-75 
3-75 
3-75 

7-7 
4-5 
0-6 
0 

6-4 
5-8 
5-75 
0 

12-7 

12-3 

70 

5-0 

In  the  first  column  is  given  the  result  of  a  normal  meal 
on  the  secretion  from  the  gastric  diverticulum.  In  the  second 
column  is  given  the  amount  and  digestive  power  of  the  juice 
which  is  excited  by  the  direct  introduction  of  150  grs.  of 
meat  into  the  large  stomach  of  the  animal,  care  being  taken 
not  to  excite  in  any  way  the  nervous  reflex  mechanism.  In 
the  third  column  is  given  the  amount  and  digestive  power 
of  the  juice  which  is  evoked  by  a  sham  meal  of  200  grs.  of 
meat.  In  the  fourth  column  is  given  the  sum  of  the  last  two 
experiments.  It  wall  be  seen  that  the  total  effect  of  the 
sham  meal  j^Ziis  the  direct  introduction  of  meat  into  the 
stomach  is  almost  identical  with  the  secretion  obtained  w^hen 
the  food  is  taken  in  a  normal  way  and  allowed  to  pass  through 
the  oesophagus  into  the  stomach. 

The  second  phase  of  the  gastric  secretion  cannot  be  ascribed 


*  Pawlow,  loc.  cit.,  p.  82. 


DIGESTION    IN    THE    STOMACH.  73 

to  the  intervention  of  the  reflex  vagal  mechanism.  Since 
it  occurs  after  cutting  off  the  stomach  from  its  connec- 
tions with  the  central  nervous  system,  it  must  have  its 
causation  in  the  gastric  walls  themselves.  That  it  cannot 
be  due  to  mechanical  stimulation  is  shown  by  the  fact, 
previously  mentioned,  that  it  is  imjDOssible  by  local  stimula- 
tion of  the  mucous  membrane,  by  rubbing,  or  introduction  of 
sand,  or  any  other  method,  to  evoke  a  secretion.  Moreover,  it 
is  not  produced  by  all  sorts  of  food.  The  introduction  of 
white  of  egg,  of  starch,  or  of  bread  into  the  stomach  causes  no 
secretion.  On  the  other  hand,  if  bread  be  mixed  with  gastric 
juice  and  allowed  to  digest  for  some  time,  the  introduction  of 
the  semi-digested  mixture  into  the  stomach  evokes  a  secretion. 
We  have  already  seen  that  meat  produces  a  secretion  ;  still 
more  potent  than  meat,  however,  is  a  decoction  of  meat,  or 
bouillon,  or  Liebig's  extract  of  meat,  or  certain  preparations 
of  peptone.  Pure  albumoses  and  peptones  have  no  effect,  so 
that  the  exciting  mechanism  must  be  some  chemical  substances 
present  in  meat,  and  produced  in  various  other  foods  under 
the  action  of  the  first  gastric  juice  secreted  in  response  to 
nervous  stimuli.  Popielski  has  shown  that  this  secretion 
occurs  after  complete  severance  of  the  stomach  from  the 
central  nervous  system,  as  well  as  after  destruction  of  the 
sympathetic  nervous  plexuses  of  the  abdomen.  Since  the 
injection  of  bouillon  directly  into  the  circulation  has  no  effect, 
this  author  concludes  that  the  second  phase  of  secretion  is 
determined  by  the  stimulation  of  the  local  nerve  plexus,  and 
that  we  have  here,  in  short,  a  peripheral  reflex  action,  the 
centres  of  which  are  situated  in  the  walls  of  the  stomach 
itself.  There  is,  however,  one  possible  explanation  for  this 
second  phase  of  secretion  which  was  not  sufficiently  considered 
either  by  Pawlow  or  by  Popielski.  Although  the  peptogenic 
substances,  those    substances  which   evoke  gastric  secretion 


74  THE    PHYSIOLOGY    OF    DIGESTION. 

on  introduction  into  the  stomach,  have  no  effect  on  the  gastric 
glands  when  [injected  directly  into  the  blood  stream,  it  is 
possible  that  they  may  have  an  influence  on  the  cells  which 
line  the  cavity  of  the  stomach,  and  that  they  may  produce,  in 
these  cells,  some  other  substance  w^hich  is  absorbed  into  the 
blood,  and  acts  as  a  specific  excitant  of  the  gastric  glands.  A 
process  of  this  nature  is  known  to  occur  in  the  next  segment 
of  the  alimentary  canal,  viz.,  the  duodenum,  where  it  deter- 
mines the  secretion  of  the  pancreatic  juice  and  the  bile. 

Edkins*  has  carried  out  a  series  of  experiments  to  deter- 
mine w^hether  such  a  chemical  mechanism  may  not  also 
account  for  the  secretion  of  gastric  juice,  which  is  excited  by 
the  introduction  of  substances  into  the  stomach.  Edkins' 
experiments  w^ere  carried  out  in  the  following  way.  The 
animal,  dog  or  cat,  having  been  anaesthetised,  the  abdominal 
cavity  was  opened,  and  a  ligature  passed  round  the  lower  end 
of  the  oesophagus  so  as  to  occlude  the  cardiac  orifice  and 
effectually  crush  the  two  vagus  nerves.  A  glass  tube  was 
then  introduced  through  an  opening  in  the  abdomen  into  the 
pyloric  part  of  the  stomach,  and  fixed  in  this  position  by  a 
ligature  tied  tightly  round  the  pylorus.  The  glass  tube  was 
connected  by  means  of  a  rubber  tube  with  a  reservoir  con- 
taining normal  salt  solution  at  the  temperature  of  the  body. 
By  means  of  this  reservoir,  a  certain  amount  of  fluid  was  intro- 
duced into  the  stomach  and  kept  here  at  a  constant  pressure ; 
the  quantity  of  fluid  introduced  varied  from  30  to  50  cc.  It 
has  been  shown  by  Edkins,  as  well  as  by  von  Mering,  that  no 
absorption  of  water  or  saline  fluid  occurs  in  the  stomach.  It 
is,  therefore,  possible  to  recover  the  whole  of  the  fluid  an 
hour  after  it  has  been  introduced,  by  simply  lowering  the 
reservoir  below  the  level  of  the  animal's  body.     If  secretion 


*  Journ.  of  Physiol,  Vol.  XXXIV.,  p.  133,  1906. 


DIGESTION    IN    THE    STOMACH.  75 

of  gastric  juice  has  occurred  into  the  cavity  of  the  stomach, 
the  fluid  will  be  increased  in  amount,  and  will  contain  hydro- 
chloric acid  as  well  as  pepsin.  In  a  series  of  control  observa- 
tions, Edkins  showed  that  the  mere  introduction  of  this  fluid 
into  the  stomach  caused  no  secretion  of  gastric  juice,  the  fluid 
removed  at  the  end  of  an  hour  having  the  same  bulk  and  the 
same  neutral  reaction  as  the  fluid  which  had  been  injected. 
Edkins  then  tried  the  influence  of  injecting  substances  into 
the  blood  stream.  The  injection  of  peptone,  of  acid,  of  broth, 
or  of  dextrin  into  the  blood  stream  produced  no  secretion  of 
gastric  juice.  If,  however,  in  the  course  of  the  hour  during 
which  the  fluid  was  allowed  to  remain  in  the  stomach,  a 
decoction  made  by  boihng  pyloric  mucous  membrane  wdth 
acid,  or  with  water,  or  with  peptone,  was  introduced  in  small 
quantities  every  ten  minutes  into  the  jugular  vein,  the  fluid 
removed  at  the  end  of  the  hour  was  found  to  be  distinctly 
acid  in  its  reaction  and  to  possess  proteolytic  properties. 
The  injection  of  these  substances  had  therefore  caused  the 
secretion  of  a  certain  amount  of  gastric  juice  containing  both 
hydrochloric  acid  and  pepsin.  In  order  to  produce  this 
positive  effect,  it  was  necessary  to  employ  pyloric  mucous 
membrane,  extracts  made  by  infusing  or  boiling  cardiac 
mucous  membrane  with  any  of  these  substances  being  without 
effect.  Edkins  concludes  therefore  that  the  secondary  secre- 
tion of  gastric  juice  is  determined,  not,  as  Pawlow  and 
Popielski  imagined,  by  a  local  stimulation  of  the  reflex 
nervous  apparatus  in  the  gastric  wall,  but  by  a  chemical 
mechanism.  The  first  products  of  digestion  act  on  the 
pyloric  mucous  membrane,  and  produce  in  this  membrane 
a  substance  which  is  absorbed  into  the  blood  stream,  and 
carried  to  all  the  glands  of  the  stomach,  where  it  acts  as  a 
specific  excitant  of  their  secretory  activity.  This  substance 
may  be  called  the  gastric  secretin  or  gastric  hormone.     It  is 


76  THE    PHYSIOLOGY    OF    DIGESTION. 

note^Yortlly  that  it  is  produced  in  that  portion  of  the  stomach 
where  the  process  of  absorption  is  most  pronounced. 

The  normal  gastric  secretion  is  therefore  due  to  the  co- 
operation of  two  factors.  The  first  and  most  important  is  the 
nervous  secretion,  determined  through  the  vagus  nerves  by 
stimulation  of  the  mucous  membrane  of  the  mouth,  or  by  the 
arousing  of  appetite  in  the  higher  parts  of  the  brain.  The ' 
second  factor,  which  provides  for  the  continued  secretion  of 
gastric  juice  long  after  the  mental  effects  of  a  meal  have 
disappeared,  is  chemical,  and  depends  on  the  production  in 
the  pyloric  mucous  membrane  of  a  specific  substance  or 
hormone,  which  acts  as  a  chemical  messenger  to  all  parts 
of  the  stomach,  being  absorbed  into  the  blood  and  thence 
exciting  the  activity  of  the  various  secreting  cells  in  the 
gastric  glands. 

It  is  still  a  moot  point  whether  this  gastric  hormone  is 
formed  only  in  the  pyloric  mucous  membrane,  or  whether  it 
may  not  be  also  produced  in  the  lower  sections  of  the  gut. 
Popielski  has  stated  that  the  introduction  of  bouillon  into  the 
small  intestine  excites  a  secretion  of  gastric  juice  in  animals, 
even  after  extirpation  of  the  abdominal  sympathetic  plexuses 
and  division  of  both  vagi.  On  the  other  hand,  introduction  of 
the  same  substance  into  the  large  intestine  has  no  influence 
on  gastric  secretion.  Popielski  ascribes  this  secretion  again 
to  a  local  reflex ;  but  it  is  more  probable  that  the  mechanism 
in  this  case  is  the  same  as  that  involved  in  the  secretion 
which  is  excited  by  the  presence  of  semi-digested  food  in  the 
stomach  itself. 

Pawlow^  has  show^n  that  the  second  phase  of  the  gastric 
secretion  is  largely  influenced  by  the  character  of  the  contents 
of  the  stomach.  Thus  the  ingestion  of  large  quantities  of  oil 
diminishes  considerably  the  amount  of  gastric  juice  secreted, 
and  Pawlow  has  suggested  the  administration  of  oil  or  oily 


DIGESTION    IN    THE    STOMACH.  77 

foods  as  a  possible  remedy  in  cases  where  the  production  of 
gastric  juice,  and  especially  of  hydrochloric  acid,  is  in  excess. 
It  has  long  been  imagined  that  the  secretion  of  gastric  juice 
was  stimulated  by  the  taking  of  alkalies.  This  idea  has  been 
shown  by  Pawlow  to  be  erroneous.  Whereas  the  formation  of 
gastric  juice  is  increased  by  the  administration  of  acids, 
especially  after  a  meal,  it  is  largely  diminished  by  the  admi- 
nistration of  alkalies  such  as  sodium  bicarbonate.  In  fact, 
sodium  bicarbonate  diminishes  the  activity  of  the  digestive 
glands  throughout  the  alimentary  tract,  and  can  be  used  as  a 
means  of  diminishing  the  secretion  of  gastric  juice  as  well  as 
the  secretion  of  .pancreatic  juice. 

A  further  important  question  has  been  j)i'opounded  by 
Pawlow ;  namely,  whether  there  is  any  alteration  in  the  con- 
stitution and  amount  of  gastric  juice  with  variations  in  the 
character  of  the  food.  So  far  as  concerns  the  first  phase  of 
secretion,  the  psychical  or  '  appetite  '  juice,  this  observer  has 
shown  that,  whatever  the  previous  diet  of  the  animal,  this  juice 
always  has  the  same  characters,  the  same  digestive  power,  and 
the  same  percentage  of  hydrochloric  acid.  He  finds  however 
that  in  the  case  of  the  second,  or  what  we  may  call  '  chemical ' 
secretion,  i.e.  that  produced  by  local  changes  in  the  stomach, 
there  is  considerable  variation  in  the  nature  of  the  juice.  In 
the  following  table  are  shown  the  relative  effects  of  meat  and  of 
milk,  when  introduced  into  the  large  stomach,  in  determining 
a  flow  of  juice  from  the  small  stomach  of  an  animal  with  a 
Pawlow  fistula.  Whereas  the  secretion  of  juice  is  greatest  in 
amount  with  the  meat,  the  digestive  power  of  the  juice  is 
greatest  with  the  bread,  and  Pawlow  regards  these  differences 
in  the  juice  as  determined  by  the  variations  in  the  stimulus 
applied  to  the  gastric  mucous  membrane.  It  is  doubtful  how- 
ever whether  these  results  justify  us  in  ascribing  a  number 
of  specific  sensibihties  to  the  gastric  mucous  membrane.     We 


78 


THE    PHYSIOLOGY    OF    DIGESTION. 


have  seen  that  the  psychical  juice  depends  merely  on  appetite, 
and  therefore  will  be  greater  in  amount  the  more  welcome  the 
food  is  to  the  animal.  On  the  other  hand,  the  juice  secreted  in 
the  second  phase  must  vary  according  to  the  quantity  of  gastric 
hormone  produced  in  the  pyloric  mucous  membrane,  and  there- 
fore with  the  nature  and  amount  of  the  substances  produced  in 
the  preliminary  digestion  of  the  gastric  contents  by  means  of 


Hours. 

Gastric  secretion  after 

100  grs.  meat. 

Two  experiments. 

Hours. 

Gastric  secretion  after 

600  cc.  milk. 

Two  experiments. 

Quantity  of  juice. 

Quantity  of  juice. 

1 

11-2       .  .       12-6 

1 

8-75     .  .         8-25 

2 

8-2       .  .         8-0 

2 

7-5       . .         6-0 

3 

4-0       .  .         2-2 

3 

22-5       .  .       23-0 

4 

1-9                  11 

4 

9-0       .  .         6-25 

5 

O'l        .  .       a  drop 

5 

20       ..         1-5 

Total 

25-4       .  .       23-9 

Total 

49-75     . .       45-0 

the  psychic  juice.  The  amount  of  juice  may  vary  also  with 
the  salts  contained  in  the  food,  according  to  their  alkaline  or 
acid  character,  and  the  percentage  of  pepsin  in  the  juice  may 
vary  with  the  intensity  of  stimulus  as  well  as  with  the  quantity 
of  fluid  available  for  the  formation  of  the  gastric  juice.  These 
factors  will  co-operate  in  determining  the  characters  of  the 
whole  juice  secreted  after  any  given  meal,  and  it  seems  pos- 
sible to  explain  the  variations,  observed  on  such  different  diets 
as  meat  and  bread,  without  having  recourse  to  the  difficult 
assumption  of  a  specific  sensibility  of  the  gastric  mucous 
membrane  to  such  inert  substances  as  starch,  dextrin,  or  egg 
albumen. 


DIGESTION    IN    THE    STOMACH.  79 

The  second  phase  of  secretion  will  continue  so  long  as  there 
are  substances  present  in  the  stomach  to  act  upon  the  pyloric 
mucous  membrane.  As  the  food  is  gradually  digested,  and 
transformed  from  a  semi-solid  into  a  soluble  condition,  the 
fluid  portions  are  squeezed  into  the  pyloric  end.  Here  a  series 
of  waves  of  contraction  are  slowly  passing  from  the  transverse 
band  towards  the  pylorus.  As  these  waves  arrive  at  the 
pyloric  orifice,  the  sphincter  surrounding  this  orifice  relaxes 
for  a  short  time,  and  a  portion  of  the  fluid  is  squirted  into  the 
first  part  of  the  duodenum.  Tlie  arrival  of  the  acid  chyme  in 
the  duodenum  sets  up  a  local  nervous  reflex  which  causes 
contraction  of  the  pylorus,  and  this  orifice  remains  closed 
until,  by  the  operation  of  the  process  which  we  shall  study  in 
the  next  lecture,  the  acid  chyme  in  the  duodenum  is  neutra- 
lised by  the  pouring  out  into  the  gut  of  alkaline  digestive  juices. 
Digestion  in  the  stomach  wall  therefore  continue  until  the 
whole  of  the  gastric  contents  are  reduced  to  a  fluid  condition, 
and  have  been  passed  by  the  contractions  of  this  viscus  into 
the  small  intestine  ;  the  pylorus,  towards  the  end  of  digestion, 
relaxing  so  as  to  allow  the  passage  of  even  solid  indigestible 
morsels  of  food  into  the  duodenum. 


LECTFEE  Y 


PA2SCBEATIC    SECRETION. 


The  nnid  cliYme  on  ent-ering  the  duodenum,  the  lii'st  part 
of  the  small  intestine,  is  subject  at  once  to  the  influence  of  the 
secretions  of  three  different  sets  of  glands,  namely :  (1)  The 
intestinal  glands,  including  those  characteristic  of  the  duodenum 
named  Brrmner's  glands  ;  (2)  The  pancreas  ;  (3)  The  Hver. 
The  ducts  of  the  two  latter  in  many  animals  have  a  common 
opening  into  the  duodenum,  and  in  every  case  there  is  a 
co-operation  between  all  three  juices  for  the  production  of  the 
intestinal  digestive  fluid.  In  discussing  the  mechanism  of 
secretion  of  these  juices,  it  will  be  more  convenient  to  take 
each  kiud  of  gland  separately. 

The  pancreas  resembles  the  saHvary  glands,  in  that  it  is 
composed  of  a  mass  of  tubules,  which  pour  their  secretions  into 
a  common  duct  opening  ruto  the  duodenum.  It  is  therefore 
easy  to  establish  a  temporary  pancreatic  fistula,  by  isolatiug 
the  duct  jnst  before  it  joins  the  iutestine,  and  uisertiug 
a  small  tube  or  canuula  into  it.  A  permanent  fistula  of  the 
pancreas  can  be  also  established  without  difficulty.  Indeed 
this  operation  is  one  of  the  earliest  in  the  history  of  experi- 
mental physiology.  De  Graaf  in  his  paper  "  De  Succo 
pancreatico,"  published  in  1677,  describes  a  method  for  the 
formation  of  a  pancreatic  fistula,  and  gives  a  figure  of  an 
aniTTial  in  which  both  saHvary  and  pancreatic  fistulae  had 
been  established.  The  juice  in  each  case  was  collected 
in  small  glass  vessels  tied   to   the  tubes  which   had    been 


PANCREATIC    SECRETION. 


81 


introduced  into  the  ducts  (Fig.  7).  Claude  Bernard  employed  a 
method  resembling  very  closely  that  of  de  Graaf.  Instead 
however  of  opening  the  intestine  as  in  the  procedure  of  the 
latter,  he  inserted  a  small  metal  cannula  into  the  duct  outside 
the  intestine  and  secured  the  cannula  in  the  abdominal  wound. 
To  the  outer  end  of  the  tube  was  tied  a  little  rubber  bag,  so 


Fig.  7. — Reproduction  of  Plate  from  Rene  de  Graaf's  treatise  "  De 
Succo  pancreatico,"  representing  a  dog  in  which  he  had  established  both 
salivary  and  pancreatic  fistulae,  small  glass  phials  being  attached  to  each 
to  collect  the  secretions  (from  "  Regneri  de  Graaf  Opera  Omnia."  Lugd. 
Batav.  1677). 

that  any  juice,  spontaneously  secreted,  could  be  collected  and 
drawn  off  at  intervals  for  examination.  The  best  method  for 
the  establishment  of  a  permanent  fistula  is  that  devised  by 
Pawlow.  A  small  quadrilateral  piece  of  the  wall  of  the 
duodenum  is  excised,  the  position  of  the  incision  being  chosen 
so  that  the  papilla,  with  the  orifice  of  the  pancreatic  duct,  may 
lie  immediately  in  the  centre  of  the  mucous  membrane  covering 
the  excised  piece.   The  integrity  of  the  intestine  is  then  restored 


P.D. 


G 


82  THE    PHYSIOLOGY    OF    DIGESTION. 

by  suturing  the  margins  of  the  wound  in  a  direction  transverse 
to  that  of  the  gut,  and  the  excised  piece  of  mucous  membrane  is 
brought  to  the  surface  and  stitched  into  the  abdominal  wound. 
The  latter  rapidly  heals  up,  so  that  finally  the  animal  presents 
a  scar  on  the  abdomen,  in  the  centre  of  which  is  a  small  pink 
papilla  through  which  the  jpancreatic  juice  can  escape.  The 
juice  is  collected  by  strapping  a  funnel  on  to  the  belly  of  the 
dog,  and  connecting  a  flask  with  the  lower  end  of  the  funnel. 
Although  there  are  no  technical  difficulties  in  carrying  out 
this  operation,  the  subsequent  care  of  the  animal  demands  great 
attention.  In  the  first  place  scrupulous  cleanliness  has  to 
be  maintained  in  its  surroundings,  in  order  to  prevent  infection 
of  the  duct  with  micro-organisms,  which  may  spread  up  towards 
the  gland  and  set  up  fatal  pancreatitis.  In  the  second 
place  an  animal  cannot  continue  to  lose  large  quantities  of 
pancreatic  juice  without  suffering  seriously  in  its  nutrition^ 
Although  the  removal  of  one  of  the  chief  digestive  juices  from 
the  gut  may  be  partly  responsible  for  this  condition,  the  loss 
of  the  juice  itself  seems  to  be  a  still  more  serious  factor.  The 
full  results  of  this  loss  can  be  mitigated  and  largely  prevented 
by  keeping  the  animals  on  a  bread  and  milk  diet,  and  by 
administration  of  daily  doses  of  sodium  bicarbonate.  Not 
only  does  this  salt  replace  the  alkalies  lost  in  the  juice,  but  it 
lowers  the  total  amount  of  the  digestive  juices  which  are 
secreted,  including  both  gastric  and  pancreatic  juices.  By  this 
treatment,  therefore,  the  loss  of  pancreatic  juice  is  reduced  ta 
a  minimum. 

Another  troublesome  feature  is  that  the  pancreatic  juice,  as. 
it  flows  over  the  papilla  of  mucous  membrane,  acquires  strong 
proteolytic  properties,  and  tends  therefore  to  digest  the  skin 
and  other  tissues  in  the  neighbourhood  of  the  papilla,  so  seriously 
interfering  with  the  comfort  and  condition  of  the  animal.. 
This  must  be  prevented  in  two  ways.     In  the  first  place,  the 


PANCREATIC    SECRETION. 


83 


proteolytic  powers  of  the  juice  can  be  reduced  to  a  minimum 
by  removing  the  greater  part  of  the  mucous  membrane 
surrounding  the  papilla.  In  the  second  place,  care  must  be 
taken  that,  whenever  the  juice  is  not  being  collected,  the  animal 
is  provided  with  a  heap  of  sand  or  other  absorbent  material  in 
its  cage,  so  that  the  secretion  may  be  absorbed  and  any 
moistening  of  the  surface  of  the  abdomen  prevented. 

In  such  an  animal  the  normal  relation  of  the  secretion  of 
pancreatic  juice  to  the  process  of  digestion  can  be  determined. 
In  the  following  table  (Pawlow)  the  secretion  of  pancreatic  juice 
resulting  from  a  meal  of  600  cc.  of  milk  is  compared  with  the 
secretion  of  gastric  juice  evoked  by  the  ingestion  of  100  gr.  of 
meat.  The  gastric  secretion  was  taken  from  a  dog  having  a 
sample  stomach,  and  therefore  represents  about  y^o^h  of  the 
whole  gastric  juice.  The  pancreatic  secretion  represents,  on 
the  other  hand,  the  total  secretion  of  the  gland. 


Gastric  Secretion  after  a  meal  of 
100  gms.  Meat.     Two  Experiments. 

Pancreatic  Secretion  after  a  meal  of 
600  cc.  Milk.     Two  Experiments. 

Hour  after 
Feeding. 

Quantity  of  Juice  in  cc. 

Hour  after 
Feeding. 

Quantity  of  Juice  in  cc. 

1st       .. 
2nd     .. 
3rd     .. 
4th     .. 
5th     .. 

11-2       . .       12-6 
8-2       . .         8-0 
40       .  .         2-2 
1-9       ..         I'l 
0-1                a  di-op. 

1st       .. 
2nd     .  . 
3rd     .  . 
4th     .. 
5th     .. 

8-75     . .         8-25 
7-5       .  .         6-0 
22-5       .  .       23-0 
9-0       . .         6-25 
20       .  .         1-5 

Total 

25-4       .  .       23-9 

Total 

49-75     .  .       45-0 

It  will  be  noticed  that,  whereas   the   greatest   quantity  of 
gastric  juice  is  poured  out  in  the  first  hour  after  the  meal, 

g2 


84  THE    PHYSIOLOGY    OF    DIGESTION. 

the  maximum   flow  of  pancreatic  juice  occurs  in  the  third 
hour,  at  a  time,  that  is  to  say,  when  (on  this  diet)  the  largest 
amount  of  chyme  is  passing  from  the  stomach  into  the  duo- 
denum.    There  must  be  some  causal  relationship  between  the 
passage  of  the  food  through  the  pylorus  and  the  secretion  of 
pancreatic  juice.     It  is  only  of  late  years  that  the  nature  of 
the  connection  between  these  two  events  has  been  brought  to 
light.     It  was  shown  long  ago  by  Bernard  that  a  flow  of  juice 
could  be  provoked  by  the  introduction  of  ether  into  the  stomach 
or  intestine.     This,  as  well  as  the  flow  occurring  when  the 
acid  chyme  passed  into  the  duodenum,  was  ascribed  to  the 
intermediation   of   a    reflex    arc  ;    but   much   difficulty   was 
experienced   in   the  search   for   the   channels   of  the   reflex. 
Thus  Heidenhain,  who  devoted  special  attention  to  this  point, 
was   unable   to   produce  any  secretion  by  stimulation  of  the 
vagus  or  splanchnic  nerves,  and  though,  in  a  few  cases,  some 
secretion  was  obtained  on  stimulation  of  the  medulla  oblongata, 
the  results  were  quite  inconstant.     Pawlow  ascribed  the  failure 
of  previous  experimenters  to  the  unphysiological   conditions 
under  which  their  operations  were  carried  out.     Here,  as  in 
the  stomach,  he  imagined  that  it  was  necessary  to  operate  on 
an  animal  unpoisoned  by  ansesthetics,  with  a  normal  blood 
pressure,  and  free  from  pain  or  discomfort,  and  that  the  ill 
success  of  previous  observers  was  due,  either  to  the  existence 
of  these  disturbing  factors,  or  to ,  the  actual  inhibition  of  the 
glandular  activity  by  reflex  means.     When,  by  the  employment 
of  methods  similar  to  those  I  described  in  the  case  of  the 
stomach,  Pawlow    avoided  the  possibility  of  such  disturbing 
factors,  he  succeeded  in  obtaining  on  stimulation  of  the  vagus 
a  flow  of  pancreatic  juice.     In  a  few  cases  a  similar  flow  was 
obtained  on  stimulation  of  the  splanchnic  nerves,  and  Pawlow 
therefore  regarded  pancreatic  secretion  .as  determined,  either 
reflexly  or  psychically  through  the  cortex,  by  impulses  leaving 


PANCREATIC  SECRETION.  85 

the  central  nervous  system  and  travelling  to  the  gland  along 
one  of  these  two  sets  of  nerves. 

It  is  difficult,  however,  in  the  case  of  the  pancreas  to  be 
certain  of  the  existence  of  a  real  psychical  secretion.  There 
is  no  doubt  that  a  flow  of  juice  may  be  observed  within  three 
or  four  minutes  of  the  taking  of  food,  but  it  is  difficult  to 
eliminate  in  this  case  the  possibility  of  some  motor  reaction 
of  the  stomach  having  driven  a  certain  amount  of  acid  juice 
into  the  beginning  of  the  small  intestine,  and  therefrom  started 
reflexly  a  flow  of  pancreatic  juice.  The  most  potent  method 
of  producing  a  flow  of  juice  is  the  introduction  of  acid  into  the 
duodenum  or  small  intestine,  and  this  method  has  until  lately 
been  adopted,  whenever  it  has  been  desired  to  obtain  pan- 
creatic juice.  The  importance  of  this  long  reflex  arc,  namely 
from  intestine  to  central  nervous  system  and  back  along  vagus 
or  splanchnics,  was  later  much  diminished  by  the  work  of 
Wertheimer*  of  Lille,  as  well  as  of  Popielski,!  a  pupil  of 
Pawlow.  Both  these  observers  showed  that  the  secretion  of 
juice,  evoked  by  introduction  of  acid  into  the  small  intestine, 
was  absolutely  unaftected  by  division  of  both  vagus  and 
splanchnics,  by  excision  of  the  spinal  cord,  or  by  extirpation 
of  the  abdominal  sympathetic.  They  therefore  regarded  the 
secretion  as  being  due  to  a  local  reflex,  started  in  the  mucous 
membrane  of  the  gut,  and  travelling  thence  to  the  collections 
of  ganglion  cells  w^hich  are  found  in  large  numbers  in  the 
pancreas.  These  collections  acted  as  reflex  centres  which 
transmitted  secretory  impulses  directly  to  the  cells  of  the 
pancreas. 

This  explanation  was  of  considerable  interest  to  Bayliss 
and  myself,  since  we  had  been  lately  studying  the  local  motor 


"^  Wertheimer,  Compt.  rend.,  cxxix.  19.  p.  737,  1899. 
t  Popielski,  Pfliiger's  Archiv.,lxxxYi.  p.  215. 


86  THE    PHYSIOLOGY    OF    DIGESTION. 

reflexes  of  the  intestine,  and  we  therefore  instituted  a  research 
with  a  view  to  determining  the  conditions  and  paths  of  this  local 
secretory  reflex.  The  research  was  rendered  easier  by  the  fact, 
discovered  by  Wertheimer,  that  the  intensity  of  the  secretion, 
evoked  by  the  introduction  of  acid  into  the  small  intestine, 
diminished  the  further  down  in  the  gut  the  acid  was  intro- 
duced. The  greatest  flow  was  obtained  when  the  acid  was 
injected  into  the  duodenum,  while,  if  it  were  introduced  into 
a  loop  composed  of  the  lowest  foot  or  two  of  ileum,  no  secretion 
whatever  was  obtained.  In  one  experiment,  therefore,  we 
ligatured  a  loop  of  the  upper  part  of  the  jejunum  at  two 
ends,  and  then  introduced  25  cc.  of  '4  per  cent.  H.Cl.  A  flow 
of  pancreatic  juice  was  obtained.  We  then  proceeded  to  destroy 
all  possible  nervous  connections  between  this  loop  and  the 
pancreas.  Both  splanchnics  and  vagi  were  divided,  the 
abdominal  sympathetic  ganglia  round  the  big  vessels  extir- 
pated, and  all  the  nerve  filaments  travelling  along  the  vessels 
to  the  ligatured  loop  were  dissected  away.  The  mesentery  was 
divided  at  the  same  time,  so  that  the  loop  of  intestine  was 
connected  to  the  rest  of  the  body  only  by  its  blood  vessels. 
Acid  was  then  introduced  for  a  second  time  into  the  lumen  of 
the  gut  (cp.  Fig.  8).  Although  all  nervous  connections  between 
gut  and  pancreas  had  been  destroyed,  the  reaction  was  the  same 
as  in  a  normal  animal,  and  a  copious  flow  of  pancreatic  juice 
was  obtained.  This  experiment  proved  at  once  that  there 
could  be  here  no  question  of  a  nervous  reflex,  either  central  or 
peripheral,  but  that  the  connection  between  mucous  membrane 
and  pancreas  must  be  chemical  and  be  effected  through  the 
blood.  We  knew  already,  from  Wertheimer's  researches,  that 
the  direct  introduction  of  acid  into  the  blood  produced  no 
flow  of  pancreatic  juice.  What  was  the  difference  between 
the  introduction  of  acid  into  the  gut,  which  did  produce 
a  flow,  and   its   introduction  into  the  blood,  which  did  not 


PANCREATIC  SECRETION.  87 

produce  any  flow  ?  The  sole  difference  must  lie  in  the  layer 
of  epithelial  cells,  which  intervene  between  the  lumen  of  the 
gut  and  the  capillary  blood  vessels  in  the  intestinal  villi.  In 
these  cells  some  substance  must  be  produced  under  the  action 
of  acids  which,  on  absorption  into  the  blood,  acts  as  the 
chemical  messenger  to  the  pancreatic  cells.  The  testing  of 
this  hypothesis  was  very  easy.  The  loop  of  intestine  was  cut 
out,  the  cells  lining  its  mucous  membrane  scraped  off  and 


Fig.  8. — Effect  of  injection  of  acid  into  loop  of  small  intestine  after 
destruction  of  its  nervous  connections.  Upper  curve — blood  pressure. 
Uppermost  of  three  lines — drops  of  pancreatic  juice  secreted.  Middle 
line — signal  marking  injection  of  50  cc.  0*4  per  cent.  HCL  Lowest  line — 
time  in  10".     Blood  pressure  zero — level  of  time  marker. 

pounded  up  with  some  of  the  dilute  hydrochloric  acid.  This 
extract  w^as  filtered,  and  the  injection  of  the  filtrate  into  the 
animal's  veins  was  found  to  produce  a  flow  of  juice  even 
greater  than  that  excited  by  the  introduction  of  acid  into  the 
lumen  of  the  gut.  This  substance,  formed  in  the  cells  under 
the  influence  of  the  acid,  we  have  called  secretin.  It  can  be 
prepared  from  the  upper  part  of  the  intestine  of  any  animal 
belonging  to  the  class  of  vertebrata  by  scraping  off  the 
mucous  membrane,  pounding  it  up,  and  boiling  with  dilute 
hydrochloric  acid.  When  the  mixture  is  boiling  it  is  nearly 
neutralised,  so  as  to  precipitate  coagulable  proteids,  and  then 


88  THE    PHYSIOLOGY    OF    DIGESTION. 

filtered.  The  filtrate  may  be  introduced  into  the  veins  of  any 
animal,  and  will  in  every  case  produce  a  flow  of  pancreatic 
juice,  whether  the  animal  be  frog,  bird,  or  mammal,  and  what- 
ever be  the  origin  of  the  secretin  solution.  We  have  not  yet 
succeeded  in  isolating  the  secretin  itself.  The  fact  that  it  is 
not  destroyed  by  boiling  shows  it  is  not  a  ferment.  It  is 
diffusible  ;  it  is  soluble  in  alcohol  or  alcohol  and  ether.  It  is 
however  very  readily  oxidised,  and  this  fact  makes  it  difficult 
to  concentrate  its  solutions  by  evaporation.  It  is  not  thrown 
down  by  any  of  the  reagents  used  for  the  precipitation  of 
bases  or  proteids.  Secretin  may  be  formed  from  mucous 
membrane  by  the  action  of  any  acids,  or  even  by  simply 
boiling  the  tissue  with  water.  On  the  other  hand  mere 
extraction  with  cold  water  or  alcohol  in  which  secretin  is  freely 
soluble,  does  not  result  in  the  production  of  an  active  solution. 
We  may  therefore  conclude  that  the  epithelial  cells  lining  the 
gut  contain  a  body — pro-secretin — which  is  insoluble  in  water, 
alcohol,  or  salt  solution,  but  which,  under  the  influence  of 
agents  such  as  acids,  undergoes  hydrolysis  with  the  splitting 
off  of  a  new  body — secretin  (Fig.  9).  That  this  chemical 
mechanism  is  normally  involved  in  the  production  of  pan- 
creatic secretion  and  is  responsible  for  the  flow  obtained  on 
the  introduction  of  acid  into  the  small  intestine,  is  shown  by 
the  fact  that  its  distribution  in  the  gut  exactly  corresponds 
with  Wertheimer's  results.  Thus,  whereas  extraction  of  the 
mucous  membrane  of  the  duodenum  yields  a  very  strong 
solution  of  secretin,  a  similar  acid  extract  or  decoction  of  the 
lower  two  feet  of  ileum  yields  a  solution  which  has  no  influence 
on  the  pancreas. 

We  have  here  an  example  of  a  type  of  mechanism  which 
probably  plays  an  important  part  in  the  correlation  of  activities 
of  many  organs  of  the  body.  In  the  normal  life  of  the  higher 
animals,  which  must  be  considered  as  a  continuous  series  of 


PANCREATIC    SECRETION. 


89 


reactions  to  changes  in  the  environment,  ending  only  with  the 
death  of  the  animal,  those  reactions,  which  are  carried  out 
through  the  intermediation  of  the  nervous  system,  play  such 
a  preponderant  part,  that  we  have  almost  forgotten  the 
possibility  of  other  means  of  co-adaptation  among  the  different 
organs  of  the  body. 

Yet,  in  the  lowest  organisms,  before  the  appearance  of  any 


!  i|. 

li  t  Mb:  i 


1  ,P 

1      :     >3l??-i)r 


r^l^Fi''iflil!lji|i'ii^^ 


—  l.Jt  i-Ui-UJUiiii_»i.it-.4.;*..iJii :.. .  »4  i^n-ij.*  i_i  c_._x_i — j^i__;./.-i„^ — i— u.- 


Fig.  9. — Effect  of  secretin  prepared  by  the  action  of  dilute  acid  on 
intestinal  mucous  membrane  which  had  been  extracted  with  hot  absolute 
alcohol.  The  effect  on  the  pancreas  is  the  same  as  with  the  extract  of 
fresh  mucous  membrane,  but  the  alcohol  has  removed  the  substance 
responsible  for  the  fall  of  blood  pressure,  which  generally  follows  the 
injection  of  fresh  extracts. 

central  nervous  system,  it  is  by  chemical  means  that  any 
co-ordination  of  function  is  determined,  either  among  the 
different  organisms  of  a  colony,  or  among  the  various  cells 
making  up  a  multicellular  organism  such  as  the  sponge.  In 
this  case  the  mechanism,  which  determines  the  movement  of 
phagocytic  cells  towards  an  irritant,  the  chase  of  food,  the 
escape  from  noxious  environment,  or  the  approach  of  sexual 


90  THE    PHYSIOLOGY   OF    DIGESTION. 

cells,  has  been  given  the  name  of  chemiotaxis.  Since  the 
application  of  these  chemical  stimuli  depends  on  their  diffusion 
through  the  medium  bathing  the  cells,  the  process  is  neces- 
sarily a  very  slow  one.  So  far  as  the  communication  of  one 
cell  with  another  in  the  same  organism  is  concerned,  the  pro- 
cess could  be  quickened  by  the  circulation  of  a  common  nutrient 
fluid  such  as  the  blood.  Before  the  appearance  of  such  a  vas- 
cular system,  however,  we  find  that  the  need  for  quick  reactions 
has  determined  the  setting  apart  of  special  reactive  cells, 
endowed  with  a  sensibility  above  that  of  their  fellows,  and  united 
with  the  surface  and  the  various  tissues  of  the  body  by  strands 
of  jDrotoplasm,  specially  endowed  with  conducting  powers 
(nerve  fibres).  The  whole  history  of  the  evolution  of  the 
higher  types  of  animal  henceforward  centres  about  this  nervous 
system.  It  is  only  in  respect  of  the  com^Dlexity  of  his  nervous 
reactions  that  man  himself  has  any  advantage  over  the  lower 
animals  or  plants.  The  development,  however,  of  a  special 
nervous  system,  adapted  for  the  carrying  out  of  quick  reactions 
to  changes  in  the  environment,  has  not  abrogated  the  more 
lowly  and  primitive  method  for  co-ordinating  the  activities  of 
different  parts  of  the  body.  Where  the  necessity  does  not 
exist  for  a  specially  rapid  reaction,  as  for  instance  in  the 
adaptation  of  the  activities  of  the  digestive  glands  to  the 
presence  of  food  in  the  alimentary  tract,  one  might  expect  to 
find,  as  we  have  found,  that  the  connection  between  the  part 
of  the  body  receiving  the  stimulus  and  the  part  of  the  body 
which  has  to  react  to  the  stimulus  should  be  by  chemical 
means.  Of  these  chemical  messengers  or  hormones,  as  they 
may  be  termed  (from  6p/xaw,  arouse  or  excite),  we  already  know 
several  examples.  The  hormones  determining  gastric  and 
pancreatic  secretion  we  have  dealt  with  in  these  last 
two  lectures.  We  shall  come  across  evidence  later  on  for  the 
existence  of  similar  bodies,   which    determine   the  secretory 


PANCREATIC  SECRETION.  91 

activity  both  of  the  Hver  as  well  as  of  the  intestinal  glands. 
The   suprarenal    bodies    manufacture    in    their    medulla    a 
substance — adrenalin — which,  travelling  over  the  whole  body, 
seems  to  be  a  necessary  condition  for  the  excitation  of  any 
sympathetic  nerves.     In  the  absence  of  this  substance  there  is 
a  fall  of  blood  pressure  which  is  fatal  within  a  very  short  time. 
The  thyroid  gland  in  the  same  way  manufactures  some  sub- 
stance, perhaps  thyro-iodin,  which  is  necessary  for  the  proper 
growth   of   the   tissues   of   the   body   and  especially  for   the 
discharge   of    the    cerebral    function.        The    foetus    during 
pregnancy  appears  to  secrete  into  the  maternal   blood  some 
chemical  substance  which  excites  the  growth  of  the  mammary 
glands.     It  is  probable  that  with  increasing  knowledge  the 
list  of  these  messenger  substances  will  be  largely  extended 
and  that,  with  their  isolation,  we  shall  have  at  our  command 
means  of  influencing  the  growth  and  activity  of  the  majority 
of  the  organs  of  the  body.     It  is  worthy  of  note  that  these 
substances  do  not  belong  to  the  group  of  physiologically  active 
agents  of  complex  and  indefinite  chemical  comj)osition,  such  as 
the  ferments  and  toxins,  but  are  in  all  probability  well  defined 
chemical    substances,   highly   unstable   in   most    cases,    but 
capable  of  analysis  and,  in  some  cases  at  any  rate,  of  artificial 
synthesis.     They  are  comparable   in   many  respects   to   the 
alkaloids  and  other  substances  of  definite  chemical  composition, 
which  form  the  drugs  of  our  pharmacopoeia.      The  practice  of 
drugging  would  seem  therefore  to  be,  not  an  unnatural  device 
of  man,  but  the  normal  method  by  which  a  number  of  the 
ordinary  physiological  processes  of  the  organism  are  carried 
out. 

The  question  now  arises  whether  this  chemical  mechanism 
is  the  only  means  employed  in  the  body  for  the  excitation  of 
pancreatic  secretion.  We  have  seen  that  the  action  of  the 
most  effective  method  for  procuring  a  flow  of  pancreatic  juice,  i.e. 


92  THE    PHYSIOLOGY    OF    DIGESTION. 

the  introduction  of  acid  into  the  small  intestine,  is  entirely  due 
to  the  splitting  off  of  secretin  under  the  action  of  the  acid,  and 
have  given  reasons  for  regai'ding  this  as  a  hydrolytic  process. 
There  are  certain  substances,  however,  which  may  produce 
pancreatic  secretion  when  introduced  into  the  intestine,  but  do 
not  form  secretin  when  rubbed  up  with  the  mucous  membrane. 
Thus  a  flow  of  juice  may  be  obtained  by  the  introduction,  into 
a  loop  of  small  intestine,  of  oil  or  of  irritant  substances,  such 
as  ether  or  oil  of  mustard,  which  have  no  effect  in  producing 
secretin  from  the  scraped  off  mucous  membrane.  Some  light 
on  the  action  of  oil  is  thrown  by  the  observations  of  Fleig,  who 
showed  that,  if  the  mucous  membrane  be  rubbed  up  with  a 
solution  of  soap,  the  resulting  mixture  contains  secretin, 
and  will  evoke  a  pancreatic  secretion  on  introduction  into  the 
blood  stream.  This  observer  regards  the  secretin  produced 
in  this  way  as  different  from  that  j)roduced  by  the  action 
of  acid,  and  therefore  christens  it  '  sapocrinin ; '  but,  apart 
from  its  mode  of  preparation,  there  is  no  evidence  of  any 
difference  between  the  two.  Wertheimer,  moreover,  has  shown 
that  if  oil  of  mustard  be  introduced  into  a  loop  of  intestine,  and 
the  blood  from  this  loop  be  led  into  the  veins  of  a  second  dog, 
a  flow  of  pancreatic  juice  will  occur  in  the  latter,  showing 
that  the  blood  flowing  from  the  loop  contains  secretin.  It  is 
possible  that  the  action  of  oil  may  be  due  to  the  formation 
of  a  certain  amount  of  soap  as  the  oil  comes  in  contact  with 
the  mucous  membrane,  and  that  this  soap  is  responsible  for 
the  formation  of  the  secretin.  The  action  of  oil  of  mustard 
can  only  be  explained  as  a  formation  of  secretin  by  a  process 
of  hydrolysis  in  the  over-stimulated  cells  of  the  small  gut, 
2)erhaps  as  one  of  the  stages  in  the  death  of  the  cells.  Whether 
the  vagus  can  still  be  credited  with  any  direct  secretory  action 
on  the  cells  of  the  pancreas  must  be  regarded  as  highly  doubt- 
ful.    The  normal  effect  of  stimulating  the  vagus  is  to  cause 


PANCKEATIC  SECRETION.  93 

movements  of  the  stomach,  and  either  relaxation  or  contraction 
of  the  pyloric  orifice.  The  fi!rst  effect,  therefore,  of  stimulating 
this  nerve  may  be  to  cause  a  flow  of  the  contents  of  the  stomach 
into  the  duodenum,  and  the  contact  of  the  acid  contents  with 
the  mucous  membrane  will  give  rise  to  the  production  of  secretin 
and  therefore  set  the  whole  chemical  mechanism  going.  When 
proper  precautions  are  taken  to  prevent  the  escape  of  fluid  from 
the  stomach  into  the  duodenum,  the  effect  on  the  pancreas  of 
stimulating  the  vagus  is  so  insignificant  that  it  can  hardly  be 
regarded  as  evidence  of  the  presence  of  secreto-motor  fibres  in 
this  nerve.  We  see  therefore  that,  whereas  in  the  mouth  the 
reaction,  which  must  be  rapid,  is  entirely  nervous,  in  the 
stomach  there  is  a  mixture  of  the  nervous  mechanism  with  the 
more  primitive  chemical  mechanism.  The  nervous  secretion 
preponderates  in  this  viscus.  When  we  come  to  the  pancreas, 
the  primitive  chemical  mechanism,  namely  the  formation  of 
hormones  and  their  circulation  through  the  blood  to  the  reactive 
tissue,  suffices  to  account  for  the  whole  activity  of  the  gland, 
and  it  is  doubtful  whether  in  this  activity  the  nervous  system 
plays  any  part  whatsoever. 


LECTUEE  VI. 

CHANGES  IN  THE  PANCREAS  DURING  SECRETION. 

Our  study  of  the  submaxillary  gland  taught  us  that  the  act 
of  secretion  involves  the  expenditure  of  energy,  which  has  its 
seat  in  the  cells  lining  the  secretory  alveoli.  This  expenditure  of 
energy  is  necessary,  not  only  for  the  formation  of  the  specific  con- 
stituents of  the  saliva  out  of  the  blood,  but  also  for  the  separation 
of  a  fluid  having  a  smaller  molecular  concentration  than  the 
plasma.  In  addition  to  this  osmotic  work,  mechanical  work 
must  be  performed  in  raising  the  pressure  in  the  duct,  if  there 
is  any  hindrance  to  the  flow  of  the  saliva.  Under  these  cir- 
cumstances the  pressure  within  the  duct  may  rise  to  a  height 
which  is  double  that  of  the  blood  in  the  arteries  supplying  the 
gland.  We  concluded  that  this  energy  must  be  determined  by 
the  changes  in  the  structure  of  the  cells,  which  give  rise  to  a 
formation  of  granules  from  the  protoplasm,  and  later  on  to 
discharge  of  these  granules  and  their  conversion  into  the  fully 
formed  secretion. 

The  chemical  changes,  that  are  concerned  in  the  transforma- 
tion of  the  food  materials  supplied  to  the  cells  of  the  pancreas 
into  the  specific  constituents  of  the  pancreatic  secretion,  may 
also  be  expected  to  involve  an  expenditure  of  energy.  In  the 
case  of  the  pancreas,  however,  there  is  no  evidence  of  work 
done  in  changing  the  molecular  concentration  of  fluid  or  in  the 
production  of  a  secretion  pressure.  If  the  duct  be  occluded, 
the  pancreatic  secretion  ceases  at  a  pressure  of  a  few  centi- 
meters H-.O,  owing  no  doubt  to  the  ease  with  which  any  fluid 


CHANGES    IN    THE    PANCREAS    DURING    SECRETION.  95 

formed  by  the  gland  cells  escapes  through  the  alveoli  mto  the 
surrounding  lymph  spaces.  The  molecular  concentration  of 
pancreatic  juice,  as  judged  by  its  freezing  point,  is  almost 
identical  with  that  of  blood  plasma. 

That  work  is  done  in  the  process  of  secretion  is  shown  by  a 
determination  of  the  amount  of  oxygen  used  up  by  the  resting 
and  by  the  secreting  gland  respectively.  Experiments  carried 
out  with  Dr.  Barcroft  have  shown  that  the  oxygen  intake  of 
the  gland  is  approximately  the  same  as  that  of  the  salivary 
gland,  and  that,  as  in  the  latter,  the  intake  is  increased  two  or 
three  fold  when  the  gland  is  made  to  secrete  by  the  intravenous 
injection  of  secretin. 

These  experiments  were  carried  out  in  the  following  way : — 

In  an  anaesthetised  dog  the  abdomen  was  opened,  and  the  vein  leading 
from  the  tail  of  the  pancreas  (which  amounts  to  about  one-sixth  of  the 
whole  organ)  was  dissected  out,  and  ligatui-es  were  so  placed  that  a 
cannula  might  be  rapidly  inserted  into  the  vein  at  a  later  stage  of  the  opera- 
tion. A  cannula  was  placed  into  the  pancreatic  duct  and  the  abdomen 
closed.  The  dog's  blood  was  then  rendered  uncoagulable  (to  prevent 
obstruction  of  the  cannula  by  clotting)  either  by  the  injection  of  leech 
extract  or  by  bleeding  the  animal  several  times,  defibrinating,  and 
returnmg  the  blood.  The  abdomen  was  then  opened,  and  a  cannula 
placed  in  the  pancreatic  vein.  The  blood  flowing  from  this  was  collected 
in  measured  vessels,  (rt)  immediately;  (6)  during  active  secretion  excited 
by  the  injection  of  secretin.  The  total  flow  per  mmute  was  also  measured. 
Corresponding  samples  of  arterial  blood  were  taken  at  the  same  time 
from  the  carotid  artery.  The  gases  from  all  these  samples  were  collected 
by  means  of  a  mercurial  pump  and  analysed,  and  the  total  gaseous 
changes  of  the  gland  were  thus  determined. 

"When  we  investigate  the  histological  changes  in  this 
gland  which  accompany  activity,  we  find  many  analogies 
with  the  corresponding  changes  in  the  salivary  glands  and 
stomach.  The  pancreas,  however,  presents  certain  peculiari- 
ties which  merit  particular  attention.  The  normal  pancreas 
consists  of  a  series  of  secretory  tubules  which  branch  out  from 
small  ducts,  the  latter  leading  into  a  few  large  ducts.    The  small 


96  THE    PHYSIOLOGY   OF    DIGESTION. 

ducts  are  lined  with  a  layer  of  narrow  hyaline  cells,  the  proto- 
plasm of  which  does  not  stain  with  either  basic  or  acid  dyes. 
At  the  point  where  a  duct  becomes  continuous  with  a  secreting 
tubule,  we  find  outside  these  hyaline  cells  a  layer  of  typical 
secreting  cells.     In  cross  section,  therefore,  such  an  alveolus 
shows  two  layers  of  cells,  the  continuation  of  the  duct  cells  in 
the  centre  being  known  as  the  centro-acinar  cells.      Towards 
the  end  of  the  alveoli  the  centro-acinar  cells  disappear,  leaving 
only  the  secreting  cells.     The  latter  in  an  ordinary  resting 
gland,  i.e.,  one  taken  from  an  animal  which  has  not  had  food 
for  twelve  to  twenty-four  hours,  show  two  well-marked  zones. 
The  outer  zone  consists  of  protoplasm  with  a  strong  affinity 
for  basic  dyes  such  as  hsemotoxylin  or  toluidine  blue.     The 
inner  zone,  i.e.,  that  turned  towards  the  lumen,  is  made  up  of 
a  mass  of  coarse  granules,  closely  packed  together,    which 
stain  intensely  with  acid  dyes  such  as  eosine.     The  nucleus, 
ivhich  is  round  and  contains  one  or  two  well-marked  acidophile 
nucleoli,  is  situated  in  the  inner  part  of  the  protoplasm  or 
basophile  zone.     If  the  gland  has  been  secreting,  the  lumen  of 
the  alveoli  contains  a  structureless  material  which,  like  the 
granules,  stains  deeply  with  eosine.    If  we  study  the  process  of 
activity   in   the  living  gland  of  the  rabbit,  as  was  done  by 
Kiihne  and  Sheridan  Lea,  we  find  that  secretion,  such  as  is  pro- 
duced by  the  injection  of  pilocarpin,  causes  a  diminution  in 
the  size  of  the  cells  and  a  discharge  of  the  granules  of  the 
inner  zone.     We  may  conclude  that  here,  as  in  the  salivary 
glands,    the   act   of   secretion   involves    some  change  in   the 
granules  and  their  discharge  from  the  cell  in   the   form   of 
secretion.     In  the  pancreas,  as  in  the  submaxillary  gland,  the 
process  of  dissimilation,  which  determines  the  formation  of  a 
secretion,  is  accompanied  by  a  process  of  assimilation,  i.e.,  the 
building  up  of  fresh  protoplasm  from  the  surrounding  lymph, 
and  its  continuous  conversion  into  secretory  granules.     It  is 


CHANGES  IN  THE  PANCREAS  DURING  SECRETION.       97 

evident  that  the  occurrence  of  changes,  such  as  I  have  described 
as  the  result  of  secretion,  signifies  a  preponderance  of  the  pro- 
cesses of  dissimilation  over  those  of  assimilation,  so  that  the 
whole  cell  gets  smaller.  This  preponderance,  however,  is  not 
a  necessary  feature  of  secretion.  In  the  heart,  for  instance, 
the  dissimilation  which  accomj^anies  contraction  is  followed 
immediately  or  attended  by  an  assimilation,  which  exactly 
balances  the  opposite  process,  so  that  the  heart  can  continue 
to  contract  throughout  the  whole  of  natural  life.  The  same 
balancing  of  two  processes  may  sometimes  be  observed  in  the 
pancreas.  Thus  in  some  cases  we  may  excite  a  copious  flow 
of  pancreatic  juice  by  the  injection  of  secretin.  Provided  that 
the  preparation  of  secretin  is  free  from  any  large  amount  of 
the  depressor  substances,  with  which  it  is  usually  contaminated, 
the  injection  may  be  repeated  time  after  time  without  inter- 
fering in  any  way  with  the  general  condition  of  the  animal. 
In  such  an  animal,  with  a  good  blood  pressure,  a  secretion  may 
be  produced  continuously  for  as  long  as  ten  hours,  and  the 
pancreas  at  the  end  of  this  time  may  react  as  well  to  the 
injections  as  it  did  at  the  beginning  of  the  experiment.  If  the 
animal  be  killed  at  the  end  of  the  experiment,  the  pancreas  to 
the  naked  eye  has  the  typical  appearance  of  a  resting  gland. 
It  is  firm,  opaque,  and  whitish.  On  microsco^^ic  examination 
the  cells  are  found  to  possess  the  two  zones  which  are  distinc- 
tive of  a  resting  gland.  In  this  case  one  must  conclude  that 
the  injection  of  this  specific  stimulating  substance,  secretin, 
has  excited  not  only  dissimilation  but  also  assimilation,  that  it 
has  in  fact  stirred  up  the  total  activities  of  the  living  cells,  so 
that  there  is  a  copious  secretion  without  any  loss  of  substance 
to  the  cells  themselves.  Usually  the  effect  of  repeated 
injections  of  secretin  is  to  cause  a  gradual  poisoning  of  the 
animal  by  the  depressor  substances,  which  are  nearly  always 
present  in  the  decoction  of  intestinal  mucous  membrane,    and 

P.D.  H 


98  THE    PHYSIOLOGY    OF    DIGESTION. 

the  consequent  diminution  of  the  circulation  interferes  with 
the  process  of  assimilation  more  than  with  that  of  activity 
or  dissimilation.  A  similar  interference  can  be  artificially 
brought  about  if  the  animal  be  bled  while  the  injections  of 
secretin  are  being  administered.  In  such  an  experiment  the 
amount  of  secretion  produced  by  each  injection  becomes  less 
and  less,  until  finally  the  gland  ceases  to  respond  at  all.  If 
the  animal  be  now  killed,  the  gland  presents  a  greyish  pink 
appearance  and  is  translucent  and  flabby.  Sections  made 
of  such  a  gland,  and  stained  with  toluidine  blue  and  eosine, 
show  a  diminution  in  the  size  of  the  cells  and  a  diminution  or 
entire  disappearance  of  the  red-staining  granular  zone. 

So  far,  then,  the  changes  in  the  pancreas  are  exactly 
analogous  to  those  in  the  salivary  gland.  Prolonged  stimula- 
tion of  the  pancreatic  cells,  however,  gives  rise  to  changes  to 
which  we  have  no  analogy  in  the  other  glands,  changes  which 
have  been  studied  in  detail  by  Dale.  The  pancreas  has  long 
been  known  to  possess,  in  addition  to  the  secretory  alveoli 
and  the  ducts,  certain  structures,  apparently  separated  from  the 
secreting  portions,  which  are  called  the '  islets  of  Langerhans.' 
These,  which  were  first  described  by  Langerhans  in  1869,  are 
roundish  areas  of  tissue,  varying  in  diameter  between  '1  and 
•24  mm.,  which  consist  of  small  polygonal  cells  with  homo- 
geneous cell  substance  and  round  nuclei  without  nucleoli. 
These  cells  take  up  any  stain  with  great  difficulty,  and  in 
ordinary  sections  can  be  seen  under  the  low  power  as  unstained 
areas  among  the  deeper  staining  alveoli.  Most  observers  have 
regarded  these  structures  as  a  tissue  distinct  from  he  secreting 
tissue  and  merely  imbedded  in  the  latter. 

Since  the  discovery  by  Minkowski  that  total  extirpation  of  the 
pancreas  gives  rise  to  a  fatal  diabetes,  this  organ  as  a  whole 
has  been  regarded  as  having  two  functions — (1)  the  secretion  of 
a  digestive  fluid  into  the  alimentary  tract;  (2)  the  secretion 


CHANGES    IN    THE    PANCREAS    DURING    SECRETION.  99 

into  the  surrounding  lymph  or  blood  stream  of  some  substance 
which  is  a  necessary  condition  for  the  utilisation  of  sugar 
in  the  body.  It  is  evident  that  the  secreting  tubules  are 
responsible  for  the  production  of  the  digestive  secretion ;  many 
physiologists  have  therefore  regarded  the  islets  as  the  organs 
for  the  production  of  the  internal  secretion.  No  evidence 
exists  in  support  of  this  notion.  A  tissue  of  unknown  origin 
has  been  accredited  with  the  equally  unknown  anti-diabetic 
function  of  the  pancreas.  Certain  Eussian  observers  have,  how- 
ever, suggested  that  these  islets  represent  phases  in  the  life 
history  of  the  secreting  alveoli,  and  that  they  are  formed  from 
the  latter  as  the  result  of  activity.  This  identity  of  origin  of 
alveoli  and  islets  receives  support  from  the  study  of  the 
structure  of  the  pancreas  in  embryos.  Laguesse  describes  the 
primitive  buds,  which  in  the  sheep  embryo  form  the  pancreatic 
rudiment,  as  being  of  the  nature  of  islets.  These  later  become 
converted  into  secondary  acini,  which  are  again  transformed 
into  islets.  The  islets,  after  growth  by  continuous  cell  division, 
are  yet  again  converted  into  a  larger  number  of  acini. 
Laguesse  regards  this  process  both  as  a  method  of  growth  and 
as  representing  an  alternation  between  external  and  internal 
secreting  {exocrine  and  endocrine)  conditions  of  pancreatic 
tissue,  and  considers  that  the  process  may  continue  to  some 
extent  throughout  life.  Dale's  investigations  confirm  the 
views  of  the  Eussian  observers.  The  islets  of  Langerhans  are 
not  independent  structures  of  separate  origin,  but  are  formed 
by  certain  definite  changes  in  the  arrangements  and  pro- 
perties of  the  cells  of  the  ordinary  secreting  tissue.  This 
change  is  gradually  accelerated  by  exhaustion  of  the  gland  by 
means  of  secretin.  As  a  result  of  such  exhaustion  there  is,  in 
the  first  place,  a  multiplication  of  the  number  of  cell  islets, 
and  finally  a  conversion  of  the  greater  part  of  the  secreting 
alveoli  into  islet  tissue.     Under  such  conditions  the  islets  no 

h2 


100 


THE    PHYSIOLOGY    OF    DIGESTION. 


longer  form  circumscribed  spots  scattered  over  the  section  but 
are  spread  diffusely  throughout  the  whole  gland. 

The   changes   are  of  such  a  kind  as  to   assimilate  all  the 


-'     ^s^ 


^^r- 


■^     y-iU- 


V' 


^shM^ 


Fig.  10. — Formation  of  islet  of  Langerlians  from  secretory  alveoli. 
Portion  of  the  pancreas  of  a  toad  in  wliich  active  secretion  had  been 
excited  by  the  injection  of  secretin.  The  islet  of  Langerhans,  with  its 
unstained  hyaUne  cells,  presents  a  marked  contrast  to  the  secretor}^ 
alveoli,  with  their  basophile  protoplasm  and  deeply-stained  zymogen 
granules.  The  islet  is,  however,  increasing  in  extent  at  the  expense  of 
the  secreting  tissue.  The  latter  in  many  places  is  losing  all  its  chromo- 
phile  elements  and  undergoing  conversion  into  islet  tissue.  In  the 
middle  of  the  islet  is  some  of  the  secretory  tissue  where  the  change 
is  not  yet  quite  complete.  (Drawn  from  a  microphotograph  of  a 
specimen  by  H.  H.  Dale.) 

cells  to  those  forming  the  epithelium  of  the  ductules  and 
the  centro-acinar  cells,  thus  bringing  about  a  reversion  to 
the  embryonic  type.     Complete    exhaustion   thus  causes,  not 


CHANGES    IN    THE    PANCREAS    DURING    SECRETION.  101 

only  an  extrusion  of  the  whole  of  the  secretory  granules, 
but  also  an  emptying  out  and  disappearance  of  the  whole  of 
the  basophile  protoplasm.  It  is  worthy  of  note  that  the 
proportion  of  islet  tissue  to  secreting  tissue  is  increased,  not 
only  by  prolonged  activity,  but  also  by  the  prolonged  inactivity 
which  occurs  during  starvation.  In  the  latter  case  the  gland, 
which  is  not  required  for  digestion,  is  called  upon  to  give  up 
its  stored  material,  whether  granules  or  protoplasm,  to  serve 
as  food  for  the  working  of  those  parts  of  the  body  whose 
continuous  activity  is  a  condition  of  the  maintenance  of  life 
— such  as  the  central  nervous  system,  the  brain,  and  the 
respiratory  muscles.  In  this  process  of  wasting,  the  same 
changes  are  brought  about  in  the  appearance  of  the  cells  as  when 
the  discharge  of  their  constituents  is  required  for  the  production 
of  a  juice  for  the  purpose  of  digestion.  Since  the  islets  are  in 
constant  process  of  formation  from  alveoli  as  the  result  of 
activity,  there  must  be  a  constant  disappearance  of  islets  and 
new  formation  of  the  alveoli  to  maintain  the  balance  between 
the  tissues.  The  embryological  evidence  brought  forward  by 
Laguesse,  as  well  as  Dale's  experiments  on  the  toad,  show 
that  pancreatic  growth  is  a  function  of  the  islets,  cell 
multiplication  being  observed  only  in  the  islets  which  are 
produced  as  a  result  of  extreme  activity.  Whether  the  pancreatic 
tissue  in  its  islet  stage  has  special  connections  with  the  carbo- 
hydrate metabolism  of  the  body,  or  whether  the  anti-diabetic 
functions  of  the  gland  are  carried  out  by  its  alveolar  cells,  in 
addition  to  and  at  the  same  time  as  their  ordinary  secreting 
functions,  we  are  not  yet  in  a  position  to  state. 


LECTUEE  VII. 

THE     PROPERTIES     OF     THE     PANCREATIC     JUICE. 

The  pancreatic  juice,  which  is  obtained  after  a  meal  from 
an  animal  with  a  permanent  fistula,  is  similar  in  all  respects  to 
that  obtained  from  one  with  a  temporary  fistula,  as  the  result 
either  of  introduction  of  acid  into  the  duodenum,  or  of  the 
injection  of  secretin  into  the  blood  stream.  It  is  a  clear  colour- 
less fluid,  somewhat  viscid,  with  a  specific  gravity  of  about  1030. 
It  contains  from  2  to  3*5  per  cent,  total  solids,  of  which  about 
1  percent,  consists  of  salts,  the  remainder  of  coagulable  proteids. 
Among  these  proteids  a  certain  proportion  are  precipitated  on 
neutralisation.  In  a  neutral  solution  about  one-half  the  total 
proteids  are  coagulated  between  55  and  60  degrees  C,  while 
the  remainder  are  coagulated  about  75  degrees  C.  The  juice 
is   always   strongly  alkaline;    10  cc.  of   juice  for  their  com- 

n 
plete  neutralisation  require  between  10  and  15  cc.  of  tt]  9;cid. 

It  is  worthy  of  note  that  the  alkalinity  of  the  juice  corre- 
sponds almost  exactly  to  the  acidity  of  the  gastric  juice. 
Thus  in  one  experiment,  70  cc.  of  pancreatic  juice,  obtained 
by  injection  of  secretin,  required  for  their  complete  neutralisa- 
tion 78  cc.  of  '4  per  cent,  hydrochloric  acid.  Each  portion 
of  chyme,  which  is  ejected  from  the  stomach  into  the 
duodenum,  will  continue  to  excite  the  production  of  secretin 
in  the  epithelial  cells  until,  under  the  influence  of  the 
absorbed  secretin,  the  pancreas  has  poured  out  an  equal 
quantity  of  pancreatic  juice,  and  the  duodenal  contents  are 


THE    PROPERTIES    OF    THE    PANCREATIC    JUICE.  103 

thus  neutralised.  The  pylorus  will  then  open  and  allow  a 
further  portion  of  acid  chyme  to  pass  into  the  duodenum,  to 
excite  in  the  same  way  the  secretion  of  a  further  equivalent 
portion  of  pancreatic  juice.  Since  under  normal  conditions 
a  secretion  of  bile  occurs  at  the  same  time  as  the  pancreatic 
secretion,  and  since  bile  has  a  certain  power  of  neutralising  the 
acid  of  the  chyme,  it  is  probable  that  under  normal  circum- 
stances the  secretion  of  pancreatic  juice  will  be  rather  smaller  in 
amount  than  the  chyme  passing  through  the  pylorus.  The 
neutralising  effects  of  these  two  juices  is  aided  moreover  by 
the  secretion  of  an  alkaline  juice  by  the  intestinal  glands. 
The  final  result  will  be  the  production  of  a  neutral  fluid  in 
the  duodenum,  and  it  is  in  this  neutral  fluid  that  the  processes 
of  intestinal  digestion  will  go  on. 

Pancreatic  juice,  obtained  in  either  of  the  above-mentioned 
ways,  contains  ferments,  which  act  as  strong  hydrolytic  agents 
on  starches  and  fats.  Starch  is  rapidly  converted  by  the 
juice  into  dextrin  and  maltose,  and  the  maltose  is  more  slowly 
transformed  into  glucose.*  The  neutral  fats  are  split  up  into 
fatty  acids  and  glycerin.  On  proteids,  juice  obtained  from  a 
temporary  fistula  has  very  slight  action.  Boiled  eggwhite  or 
gelatin  are  not  digested  even  after  weeks  of  soaking  in  the 
fluid.  Fresh  fibrin  and  caseinogen  are  slowly  digested. 
The  juice  may  therefore  be  said  to  contain  a  weak  proteolytic 
ferment,  resembling  that  which  can  be  extracted  from  almost 
any  tissue  of  the  body.  A  similar  ferment  can  be  obtained 
from  extracts  of  the  intestinal  mucous  membrane,  and  has 
been  named  by  Cohnheim  erepsin.  Its  chief  function  in  this 
situation  appears  to  be  the  further  digestion  of  albumoses  and 
peptones,  and  their  conversion  into  amino-acids.  It  seems, 
therefore,  that  the  pancreatic  cells,  produced  as  an  outgrowth 

*  The  conversion  into  glucose  takes  place  more  rapidh'  in  a  slightly  acid 
medium. 


104  THE    PHYSIOLOGY    OF    DIGESTION. 

from  the  mucous  membrane  of  the  intestine,  have  retained 
the  power  of  producing  this  weak  proteolytic  ferment  in 
common  with  the  other  cells  clothing  the  inner  surface  of 
the  gut.  These  properties  of  fresh  pancreatic  juice  were 
described  by  Claude  Bernard,  who  regarded  the  proteolytic 
functions  of  the  juice  as  unimportant.  Corvisart  however, 
working,  not  with  the  juice  as  obtained  from  a  cannula  in  the 
pancreatic  duct,  but  with  the  juice  as  secreted  into  the 
duodenum,  described  as  one  of  its  essential  properties  an 
extremely  energetic  action  on  proteids.  Most  of  the  later  re- 
searchers dealt  chiefly  with  an  extract  of  the  pancreas  itself.  All 
of  these  physiologists,  of  whom  Kiihne,  Heidenhain,  and  Langley 
may  be  specially  mentioned,  found  that  the  watery  extract 
contained  not  only  lipase  and  amylase,  but  also  a  substance 
which  rapidly  underwent  conversion  into  an  active  proteolytic 
ferment.  The  latter  was  named  trypsin,  and  its  precursor  in 
the  gland  trypsinogen.  In  the  juice  obtained  from  permanent 
fistulse,  Pawlow  found  trypsin  preformed,  but  showed  later 
that  part,  at  any  rate,  of  the  trypsin  was  present,  not  in 
the  form  of  ferment,  but  as  its  precursor  trypsinogen. 
Chepowalnikow,  working  in  Pawlow's  laboratory,  found  that 
the  proteolytic  activity  of  the  juice  was  enormously  in- 
creased by  adding  to  it  a  drop  of  intestinal  juice  or  of  an 
extract  of  intestinal  mucous  membrane.  He  therefore  con- 
cluded that  the  juice  generally  contained  tr^^psinogen,  which 
under  the  influence  of  a  ferment  etiterokinase,  contained  in  the 
succus  entericus,  was  transformed  into  the  active  ferment 
trypsin.  Now  it  must  be  remembered  that  the  juice  obtained 
by  Pawlow's  method,  before  it  is  collected,  has  to  trickle  over 
the  small  portion  of  intestinal  mucous  membrane  which  is 
left  in  the  abdominal  wall  surrounding  the  orifice  of  the  duct. 
This  mucous  membrane  can  serve  as  a  source  of  enterokinase, 
and  Delezenne  has  found  that,  if  a  cannula  be  inserted  through 


THE    PROPERTIES    OF    THE    PANCREATIC   JUICE.  105 

the  papilla  into  the  duct,  so  as  to  prevent  the  juice  coming 
in  contact  with  the  intestinal  mucous  membrane,  the  liquid 
so  obtained  contains  no  trypsin  at  all,  and  is  without  effect  on 
coagulated  proteid.  We  may  say  therefore  that  juice,  as  it  is 
secreted  normally  by  the  pancreas,  contains  no  trypsin,  but 
a  precursor  of  trypsin  named  trypsinogen.  The  trypsin ogen 
can  be  converted  into  try^Dsin,  only  by  the  action  of  the 
ferment  enterokinase  furnished  by  the  mucous  membrane  of 
the  gut.  No  other  agent  is  able  to  effect  this  transformation. 
The  spontaneous  conversion  of  the  trypsinogen,  observed  by 
the  older  workers  to  occur  in  extracts  of  the  pancreatic  gland, 
depends,  not  as.  they  thought  on  the  acidity  or  reaction  of  the 
gland,  but  on  the  accidental  defiling  of  the  tissue  with  intes- 
tinal contents  in  the  process  of  extraction  from  the  animal. 
If  care  be  taken,  in  cutting  the  pancreas  out  of  the  dead  body 
of  an  animal,  to  avoid  any  contamination  of  the  gland  with 
intestinal  contents  or  mucous  membrane,  a  watery  or  glycerin 
extract,  though  containing  trypsinogen,  will  remain  inactive 
for  months ;  but  at  any  time  it  can  be  activated  by  the 
addition  of  a  small  amount  of  enterokinase. 

As  I  have  said,  the  discoverers  of  enterokinase  looked  upon 
it  as  a  ferment  which  converted  trypsinogen  into  trypsin. 
Since,  in  this  case,  one  ferment  is  formed  by  the  action  of 
another,  Pawlow  spoke  of  enterokinase  as  the  "  ferment  of 
ferments."  More  lately  a  different  view  has  been  put  forward 
of  the  mode  of  interaction  between  these  two  bodies,  by 
Delezenne,  and  by  Dastre  and  Stassano,*  and  this  view  has 
been  accepted  by  such  authorities  as  Metchnikow  and  Ehrlich. 
According  to  them,  trypsin  is  not  a  single  body,  but  is  a 
combination  or  association  of  two  bodies,  trypsinogen  and 
enterokinase.  They  have  thought  that,  just  as  two  bodies, 
called  the  amboceptor  and  the  complement,  are  involved  in  the 

*  Archives  internat.  de  Physiol.,  Vol.,  I.,  p.  86,  1904. 


106  THE    PHYSIOLOGY    OF    DIGESTION. 

destruction  of  red  blood  corpuscles  by  foreign  sera,  so  in  the 
destruction  of  the  proteid  molecule  by  trypsin,  the  trypsinogen 
serves  simply  to  anchor  the  active  ferment,  the  kinase,  on  to 
the  proteid  molecule.     In  further  support  of  this  analogy  with 
the   phenomena    of    hsemolysis,   Delezenne   has   stated   that 
enterokinase  can  be  obtained  in  large  quantity  from  lymphatic 
glands,  as  well  as  from  the  leucocytes  of  the  blood,  and  is 
therefore  simply  one  of   the   cytases,  the  digestive  ferments 
contained  in   the   phagocytic   cells   of   the   body.      Such   an 
analogy  between  the  methods  employed  in  the  defence  of  an 
animal  against  invasion  by  foreign  cells,  and  that  employed 
in   normal  nutrition,  would  be   of  far-reaching   importance, 
and  Bayliss  and  I  have  therefore  reinvestigated  the  question. 
A  decision  between  the  two  views  is  not  difficult  to  arrive  at. 
If  trypsin  be  in  all  cases  a  combination  of  trypsinogen  and 
enterokinase,    there    must    always   be   a   certain   proportion 
between  the  quantities  of  the  two  substances  present  in  any 
active  juice,  in  order  that  it  may  exert  its  full  powers.     If  on 
the  other  hand  enterokinase  acts  simply  as  a  ferment,  it  does 
not  matter  how  small  a  quantity  of  enterokinase  is  added  to, 
the  inactive   juice   containing   trypsinogen,  provided    that  a 
sufficient  time  is  allowed  for  the  ferment  to  work.     We  have 
found  that,  as  a  matter  of  fact,  the  smallest  trace  of  entero- 
kinase is  able,  if  it  be  given  sufficient  time,  to  activate  any 
quantity  of  inactive  juice.      As  we   increase   the  amount  of 
enterokinase   added,    we   do   not    increase   in   any   way   the 
maximum  digestive  power  of  the  juice.     We  simply  hasten 
the  process  of  activation.     Moreover,  if  trypsin  always  owes 
its  activity  to  an  association  of  the  two  bodies,  it  must  always 
contain    enterokinase,    and    therefore    be    able    to    activate 
trypsinogen  to  which  it  may  be  added.     This  is  not  the  case. 
Although  certain  preparations   of   trypsin   contain  traces  of 
enterokinase  and  therefore  exert  a  small  activating  effect,  it  is 


THE  PROPERTIES  OF  THE  PANCREATIC  JUICE.       107 

possible  to  procure  specimens  of  trypsin  which  have  not  the 
slightest  activating  influence  on  fresh  pancreatic  juice. 
There  is  a  further  biological  test  which  we  can  apply  to  decide 
the  question.  Normal  serum  resists  the  digestive  action  of 
trypsin  in  consequence  of  its  content  in  a  body — antitrypsin. 
This  antitrypsin  of  serum  has  been  regarded  by  Dastre  as  an 
antikinase.  It  is  possible,  however,  to  make  antikinase  by 
injecting  an  animal  with  successive  doses  of  enterokinase. 
Such  an  antikinasic  serum  differs  entirely  from  the  normal 
antitryptic  serum.  Whereas  normal  serum,  in  most  cases,  has 
no  influence  on  enterokinase  but  annuls  the  action  of  trypsin, 
an  antikinasic  serum,  prepared  by  the  subcutaneous  injection 
of  enterokinase,  entirely  paralyses  the  activating  power  of 
enterokinase  on  trypsinogen  solutions,  but  has  no  influence 
on  the  digestive  powers  of  a  solution  of  trypsin.  Finally  it 
has  been  shown  by  Weinland,  that  intestinal  worms  owe  their 
immunity  from  digestion  to  a  substance  which  is  present  in 
their  tissues  and  which  has  the  property  of  preventing  pan- 
creatic digestion.  Weinland  regards  this  body  as  an  anti- 
trypsin, Dastre  as  an  antikinase.  It  has  been  shown  lately 
by  Hamill  that  the  antibody  extracted  from  intestinal  worms 
acts  in  all  respects  like  the  antitrypsin  of  normal  serum.  It 
has  no  effect  on  enterokinase,  and  its  inhibitory  influence  is 
limited  to  fully  formed  trypsin.  There  are  no  grounds  there- 
fore for  the  analogy  which  has  been  drawn  between  the 
interaction  of  these  two  bodies  and  the  interaction  of  the  two 
bodies  which  are  involved  in  the  solution  of  red  blood 
corpuscles.  Enterokinase  is  a  ferment  secreted  by  the 
intestinal  epithelium  and  peculiar  to  this  epithelium.  We 
have  found  it  impossible  to  extract  any  enterokinase  from 
Ij'mphatic  glands  or  indeed  from  any  tissues  other  than  those 
of  the  intestine.  There  is  no  justification  therefore  for  class- 
ing it  with  the  cytases,  and  the  results  of  our  investigations 


108  THE    PHYSIOLOGY    OF    DIGESTION. 

have  been  to  confirm  entirely  the  view  of  Pawlow,  with  regard 
to  the  action  of  this  ''  ferment  of  ferments." 


The  Qualitative  Adaptation  of  the  Pancreatic 

Juice. 

The   mechanisms   which  we  have  studied  in  the  last  few 
lectures  provide  for  a  very  extensive  adjustment  between  the 
activity  of  the  pancreas  and  the  digestive  needs  of  the  animal. 
Substances  which  are  difficult  of  digestion  will  remain  long  in  the 
stomach  and  will  probably  excite  a  greater  flow  of  gastric  juice. 
The  flow^  of  pancreatic  juice  will  be  determined  by  the  flow  of 
gastric  j  uice.     The  greater  the  amount  of  acid  chyme  entering  the 
duodenum  the  larger  will  be  the  amount  of  pancreatic  secretion. 
With  a  rapid  flow  w^e  shall  have  a  more  watery  juice,  containing 
however  the  normal  amount  of  sodium  carbonate.     The  slower 
the  flow  the  more  concentrated  in  proteid  and  in  trypsinogen 
shall  we  expect  to  find  the  juice.     According  to  Pawlow,  how- 
ever, the  activity  of  this  gland  shows  a  marvellous  qualitative 
adaptation  to  the  nature  of  the  food-stuffs.     His  pupil,  Vasilieff, 
found  that  the  ^^ancreatic  juice  obtained  from  animals  with 
permanent  fistulas  showed  variations  in  the  relative  quantities 
of  the  three  ferments  present,  according  to  the  nature  of  the 
food,  the  trypsin  being  formed  in  largest  amount  on  a  diet  of 
meat,  lipase  on  a  diet  of  fat,  and  the  amylase  on  a  diet  chiefly 
consisting  of  carbohydrates.     There  w^as  thus  a  slow  accom- 
modation of  the  pancreatic  cells  to  the  nature   of  the  food 
which  the  animal  receives.     According  to  Walther  the  adaptation 
is  still  more  rapid.     If  in  the  course  of  one  day  three  meals,  the 
first  of  milk,  the  second  of  bread,  and  the  third  of  meat,  be  eaten 
in  succession,  at  intervals  of  a  few^  hours,  the  meat  meal  will  give 
a  juice  containing  the  largest  proportion  of  trypsin,  while  the 
meal  of  bread  causes  the  secretion  of  a  juice  in  which  the 


THE  PROPERTIES  OF  THE  PANCREATIC  JUICE. 


109 


ferment  amylase  is  preponderant.     The  figures  obtained  hj 
this  observer  are  given  in  the  following  tables : 


Proteolytic 
Ferment. 

Amylolytic 
Ferment. 

Fat-splitting 
Ferment. 

Quantity 

of 

Juice. 

*    Diet. 

Strength 

of 

Juice. 

Total 

units  of 

Ferment. 

Strength 

of 

Juice. 

Total 
units  of 
Ferment. 

bo 

2 

'a  5 

Milk  600  cc. 

48  cc. 

22-6 

1085 

9 

432 

90-3 

4334 

Bread  250  gnis. .  . 

151  cc. 

131 

1978 

10-6 

1601 

5-3 

800 

Meat  100  gms.   .  . 

144  cc. 

10-6 

1502 

4-5 

648 

25 

3600 

It  will  be  seen  that,  while  their  general  statements  as  to 
trypsin  and  amylase  are  borne  out  by  these  figures,  there  is  a 
very  little  difference  between  the  lipase,  secreted  on  a  fatty  diet 
such  as  milk,  and  that  secreted  on  a  proteid  diet  such  as  meat. 
Moreover,  it  must  be  remembered  that  the  observations  of  these 
two  physiologists  were  carried  out  before  the  discovery  of 
enterokinase.  The  amount  of  trypsin  they  found  in  each 
specimen  of  juice  therefore  must  have  been  purely  accidental 
and  dependent  on  the  time  at  which  they  examined  the  proteolytic 
powers  of  the  samples.  Any  postponement  of  the  examination 
would  give  the  small  traces  of  enterokinase  a  longer  time  to 
act,  and  would  increase  the  tryptic  power  of  the  juice.  We 
have  therefore  only  the  results  on  amylase  in  support  of  the 
general  statement  as  to  the  powers  of  adaptation  presented  by 
the  pancreas.     The  subject  is  in  need  of  further  investigation.. 

Pawlow's  views  seemed  to  receive  weighty  confirmation  from 
the  results  of  an  experiment  conducted  by  Weinland.  Wein- 
land  stated  that,  whereas  the  pancreas  of  an  adult  dog  is 
free  from  lactase  (the  ferment  which  converts  lactose  into 
galactose  and  glucose),  extracts  made  from  the  gland 
of  an    animal,  taking    milk    or    milk    sugar  with    its    diet,. 


110  THE    PHYSIOLOGY    OF    DIGESTION. 

contained  this  ferment.  Here  then  was  a  definite  example 
of  adaptation — the  appearance  in  the  gland  and  presumably 
in  the  juice,  of  a  ferment,  not  previously  present,  as 
the  result  of  a  special  form  of  diet.  With  the  view  of 
determining  the  mechanism  of  this  adaptation,  Weinland's 
experiments  were  repeated  by  Bainbridge  with  the  result  that 
lactase  was  found  in  the  pancreatic  juice  after  feeding  with 
lactose  but  was  absent  unless  this  substance  were  administered. 
A  French  observer,  Bierry,  having  repeated  these  experiments 
with  absolutely  negative  results,  the  whole  subject  has  been 
reinvestigated  by  Plimmer.  For  the  purpose  of  determin- 
ing the  presence  of  lactase  in  the  juice  or  extracts  of  the 
gland,  20  to  50  cc.  of  the  extract  or  juice  were  allowed  to 
digest  for  three  days  with  a  5*0  per  cent,  solution  of  lactose, 
toluol  being  added  to  prevent  bacterial  changes.  At  the 
same  time  a  control  experiment  was  carried  out,  using  the 
identical  quantities,  but  after  previously  boiling  the  juice 
or  pancreatic  extract,  to  destroy  any  ferment  that  might  be 
present.  At  the  end  of  this  time  the  proteids  were  removed 
by  means  of  mercuric  nitrate,  the  excess  of  mercury  got  rid  of 
l)y  sulphuretted  hydrogen,  and  the  amount  of  sugar  determined 
in  both  fluids  by  means  of  Allihn's  method.  In  this  method, 
the  co^Dper  oxide,  produced  by  the  reduction  of  Fehling's 
solution,  is  collected  and  weighed,  so  that  no  scope  is  left  for 
error  of  judgment  in  determining  the  exact  moment  at  which 
the  reduction  of  Fehling's  fluid  is  completed.  In  every  case 
Plimmer  found  that  the  reduction  power  of  the  milk  sugar, 
which  had  been  treated  with  extracts  of  pancreas,  or  with 
pancreatic  juice  taken  from  animals  fed  for  weeks  on  lactose, 
was  identical  with  that  of  the  control  solution  in  which  the 
juice  or  extract  had  been  previously  boiled.  We  must  conclude, 
therefore,  that  the  pancreas  has  no  power  of  altering  its 
.secretion  in  response  to  the  presence  of  lactose  in  the  gut. 


THE  PROPERTIES  OF  THE  PANCREATIC  JUICE.        Ill 

Lactase  is  present  as  a  normal  constituent  of  the  intestinal 
mucous  membrane  (at  any  rate  in  young  animals),  so  that  there 
is  no  necessity  for  the  development  by  the  pancreas  of  the 
power  of  digesting  this  substance.  The  importance  of  Bierry's 
and  Plimmer's  results  lies  in  the  fact,  that  they  disprove 
the  one  definite  case,  in  which  we  thought  we  had  a  qualitative 
adaptation  of  the  pancreatic  secretion  to  the  nature  of  the  food. 
Popielski,  a  former  pupil  of  Pawlow,  has  himself  come  to  the 
conclusion  that,  in  the  process  of  secretion,  the  pancreas  pours 
out  the  whole  of  its  contained  ferments  or  pro-ferments,  and 
has  denied  altogether  the  power  of  adaptation  which  has  been 
ascribed  to  this  gland.  Pawlow  regards  the  adaptation  as  deter- 
mined by  a  specific  sensibility  of  the  mucous  membrane  of 
the  duodenum  to  the  different  classes  of  food- stuffs  and  the 
consequent  production  of  nerve  impulses  of  varying  qualities 
proceeding  to  the  gland.  We  have  already  seen  that  the  normal 
activity  of  the  pancreas  is  called  forth,  not  by  nervous  changes 
but  by  the  chemical  messenger,  secretin.  There  is  no  evidence 
that,  in  the  absence  of  this  mechanism,  stimulation  of  the 
mucous  membrane  of  the  intestine  can  evoke  any  pancreatic 
secretion,  and  it  is  therefore  still  more  improbable  that  a 
qualitative  adaptation  of  the  juice  to  the  type  of  food- stuff  is 
determined  by  such  a  nervous  mechanism.  There  are  riddles 
enough  in  physiology  without  conjuring  up  a  teleological  adap- 
tation for  which  the  experimental  evidence  is  inadequate,  the 
conception  of  its  mechanism  impossible,  and  which  is  not 
necessary  for  the  well-being  of  the  animal. 


LECTURE   VIII. 

THE    BILE. 

The  fact  that  the  bile,  the  secretion  of  the  liver,  is  in  so 
many  animals  poured  into  the  intestine  by  an  orifice  common 
to  it  and  the  pancreatic  juice,  suggests  that  these  two  fluids 
co-operate  in  their  actions  on  the  ingested  food-stuffs,  and  points 
to  a  direct  use  of  the  bile  in  the  processes  of  digestion.  In 
addition  to  this  function,  the  bile  must  also  be  regarded  as  an 
excretion,  representing  as  it  does  the  channel  by  which  the 
products  of  disintegration  of  haemoglobin — the  red  colouring 
matter  of  the  blood — are  got  rid  of  from  the  organism.  As 
an  excretion  the  production  of  bile  must  be  continuous,  and 
related,  not  to  the  j)i'ocesses  of  digestion,  but  to  the  intensity 
of  destruction  of  the  red  corpuscles.  On  the  other  hand  bile, 
as  a  digestive  fluid,  is  needed  in  the  gut  only  during  the 
period  that  digestion  is  going  on.  The  exigencies  of  the  body, 
therefore,  require  a  continuous  excretion  of  bile  by  the  liver, 
but  a  discontinuous  entry  of  this  fluid  into  the  small  intestine. 
This  discontinuity  in  the  entry  of  a  continuous  secretion  into 
the  intestine  is  secured,  in  the  majority  of  animals,  by  the 
existence  of  the  gall  bladder,  a  diverticulum  from  the  bile  ducts, 
in  which  all  bile,  secreted  during  the  intervals  between  the 
periods  of  digestive  activity,  is  stored  up.  In  the  horse,  where 
the  gall  bladder  is  absent,  its  place  is  taken  to  some  extent  by 
the  great  size  of  the  bile  ducts.  Moreover,  in  such  an  animal 
the  process  of  digestion  is  much  more  continuous  in  character 
than  it  is  in  carnivora.    Since  the  bile  accumulates  in  the  gall 


THE    BILE. 


113 


bladder  during  the  whole  time  that  digestion  is  not  going  on, 
and  is  only  poured  into  the  gut  during  digestion,  we  find  on 
opening  a  fasting  animal  that  the  gall  bladder  is  distended, 
whereas  in  an  animal  some  hours  after  a  meal  the  gall 
bladder  is  practically  empty. 

During  the  period  that  the  bile  secreted  by  the  liver  remains 
in  the  gall  bladder,  it  undergoes  certain  changes,  as  is  shown 
by  comparison  of  the  composition  of  bile  obtained  from  the 
gall  bladder  with  that  obtained  from  a  fistula  of  the  bile 
duct. 

Analyses  of  Bile  (Human). 


From  a  biliary  fistula  (Yeo  and  Herromi). 


From  the  gall  bladder  (Hoppe-Seyler) 
in  100  parts. 


Mucin  and  pigments   . 

0148 

Mucin 

1-29 

Sodium  taurocholate  . 

0055 

Sodium  taurocholate    . 

.     0-87 

Sodium  glycocholate  . 

0-165 

Sodium  glycocholate    . 

.     303 

Cholesterin 

' 

Soaps 

.     1-39 

Lecithin 

-  0-038 

Cholesterin 

.     0-35 

Fats 

J 

Lecithin  .  . 

.     0-53 

Inorganic  salts   . 

0-840 

Fats         

.     0-73 

Water 

98-7 

During  its  stay  in  the  bladder,  the  bile  is  concentrated  by 
the  loss  of  water  and  by  the  addition  to  it  of  mucin  or  nucleo- 
albumen,  derived  from  the  cells  lining  the  bladder.  Of  the 
other  constitutents  of  bile,  the  pigments  must  be  regarded 
simply  as  waste  products.  They  pass  into  the  intestine  and 
are  there  converted  by  the  processes  of  bacterial  reduction  into 
stercobilin,  which  is  excreted  for  the  most  part  with  the 
faeces,  a  small  proportion  being  absorbed  into  the  blood 
vessels  and  turned  out  in  a  more  or  less  altered  condition  as 
the  pigments  of  the  urine.  From  the  point  of  view  of  diges- 
tion, the  important  constituents  of  bile  are  the  bile  salts,  with 
the  lecithin  and  cholesterin  held  in  solution  by  these  salts. 
Before  we  enquire  into  the  action  of  these  essential  digestive 
constituents,  it  will   be   interesting   to    determine   the   time 

P.D.  I 


114  THE    PHYSIOLOGY   OF    DIGESTION. 

relations  of  the  secretion,  as  well  as  of  the  out-pouring  of 
bile  into  the  intestine,  in  connection  with  the  processes  of 
digestion.  These  time  relations  can  be  learnt  from  animals 
in  whom  the  bile  is  conducted  to  the  outside  of  the  body  by 
means  of  a  permanent  fistula.  In  order  to  determine  the 
time  relations  of  the  flow  of  bile  into  the  intestine,  Pawlow 
has  devised  the  following  operation  :■ — In  the  dog,  the  abdomen 
is  opened,  and  the  common  bile  duct  sought  as  it  passes 
through  the  intestinal  wall.  The  orifice  of  the  duct,  with  a 
piece  of  the  surrounding  mucous  membrane,  is  then  cut  out 
of  the  wall  of  the  intestine,  and  the  aperture  thus  made 
sutured.  The  excised  portion  of  mucous  membrane,  with  the 
opening  of  the  duct,  is  then  sewn  on  to  the  surface  of  the 
duodenum,  and  the  loop  of  duodenum  at  this  point  is  stitched 
into  the  abdominal  wound.  After  healing,  the  natural  orifice 
of  the  bile  duct  is  thus  made  to  open  on  the  surface  of  the 
abdomen. 

In  an  animal  treated  in  this  way,  the  flow  of  bile  from 
the  fistula  is  found  to  run  absolutely  parallel  to  the  pancreatic 
secretion.  Although  smaller  in  amount,  it  rises  and  falls  with 
the  latter.  Thus  a  meal  of  meat  produces  a  large  flow  of 
bile,  a  meal  of  carbohydrates  only  a  small  flow.  Moreover, 
beginning  almost  immediately  after  taking  food,  it  attains  its 
maximum  with  the  pancreatic  juice  in  the  third  hour,  and 
then  rapidly  declines. 

In  the  production  of  this  flow  of  bile,  two  factors  may  be 
involved :  (1)  the  emptying  of  the  gall  bladder ;  (2)  an  increased 
secretion  of  the  bile.  In  order  to  determine  the  relative  impor- 
tance to  be  ascribed  to  each  factor,  we  must  compare  the 
results  obtained  on  an  animal  possessing  a  Pawlow  fistula  with 
those  obtained  on  an  animal  provided  with  a  fistulous  opening 
into  the  gall  bladder,  the  common  bile  duct  in  the  latter 
having  been  ligatured  to  insure  that  the  total  secretion  of 


THE    BILE.  115 

bile  passes  out  by  the  fistula.  In  such  animals  we  find,  as  we 
should  expect,  that  the  secretion  of  bile  is  a  continuous 
process,  but  that,  synchronously  with  the  great  outpouring  of 
bile  into  the  intestine  during  the  third  hour  after  a  meal, 
there  is  an  increased  secretion  of  this  fluid.  The  passage, 
therefore,  of  the  semi-digested  food  from  the  stomach  into 
the  duodenum  causes,  not  only  a  slow  contraction  and  empty- 
ing of  the  gall  bladder,  but  also  an  increased  secretion  of 
bile  by  the  liver.  What  is  the  mechanism  involved  in  the 
production  of  these  two  effects?  The  muscular  wall  of  the 
gall  bladder,  .  as  has  been  shown  by  Dale,  is  under  the 
control  of  nerves  derived  both  from  the  vagus  and  from  the 
sympathetic,  the  former  conveying  motor  and  the  latter 
inhibitory  impulses.  It  is  usual  to  suj^pose  that  the  entry  of 
acid  chyme  into  the  duodenum  provokes  reflexly  the  contrac- 
tion of  the  gall  bladder,  but  the  exact  paths  and  steps  in  this 
reflex  act  have  not  yet  been  fully  determined.  The  increased 
secretion  of  bile,  which  is  produced  by  the  passage  of  the  acid 
chyme  through  the  pylorus,  can  be  also  evoked  by  the  intro- 
duction of  acid,  such  as  '4  per  cent.  H.CL,  into  the  duodenum, 
and  occurs  even  after  division  of  all  connection  between  the 
liver  and  the  central  nervous  system.  Since  the  presence  of 
bile  is  necessary  for  the  full  development  of  the  activities  of  the 
pancreatic  juice,  and  its  secretion  is  initiated  by  the  same  sort 
of  stimulus,  i.e.,  acid  applied  to  the  mucous  membrane  of  the 
gut,  the  question  naturally  arises  whether  the  mechanism  for 
the  secretion  of  bile  may  not  be  identical  with  that  for  the 
secretion  of  pancreatic  juice.  In  order  to  decide  this  point  we 
must  make  a  temporary  biliary  fistula,  by  inserting  a  cannula 
into  the  hepatic  duct.  A  solution  of  secretin  is  then  prepared 
from  an  animal's  intestine.  In  making  this  solution,  we  must 
be  careful  to  avoid  any  contamination  by  bile  salts,  which 
may  possibly  be  adherent  to  the  mucous  membrane  of  the 

i2 


116  THE    PHYSIOLOGY    OF    DIGESTION. 

gut  and  would  in  themselves,  on  injection,  evoke  an  increased 
secretion  of  bile.  It  is  therefore  better  to  extract  the  pounded 
mucous  membrane  with  boiling  absolute  alcohol,  until  this 
fluid,  evaporated  into  a  small  bulk,  shows  no  trace  of  bile 
salts.  The  dried  and  powdered  gut  is  then  boiled  with  dilute 
acid.  On  injecting  the  solution  of  secretin  so  obtained  into  the 
animal's  veins,  an  increased  flow  of  bile  is  at  once  produced. 
In  one  experiment,  for  instance,  we  found  that  the  injection 
into  the  veins  of  5  cc.  of  a  solution  of  secretin,  prepared  in 
this  way,  increased  the  secretion  of  bile  by  the  liver  from 
twenty-seven  drops  in  fifteen  minutes  to  fifty-four  drops  in 
fifteen  minutes  (Fig.  11).  The  rate  of  secretion  was  therefore 
doubled.  We  must  conclude  from  these  experiments  that  the 
mechanism,  by  which  the  increased  secretion  of  bile  is  pro- 
duced at  the  time  when  this  fluid  is  required  in  the  intestine, 
is  identical  with  that  for  the  secretion  of  pancreatic  juice,  and 
that  in  each  case  one  and  the  same  substance — secretin — is 
formed  by  the  action  of  the  acid  on  the  cells  of  the  mucous 
membrane,  and  that  this  secretin,  on  absorption  into  the  blood 
stream,  excites  both  the  liver  and  pancreas  to  increased 
activity. 

THE    DIGESTIVE    FUNCTIONS    OF    THE    BILE. 

Bile  contains  a  weak  amylolytic  ferment.  Its  uses  in 
digestion  are  dependent  however,  not  on  the  presence  of  this 
ferment,  but  on  the  peculiar  action  of  the  bile  salts  on  the 
fermentative  powers  of  the  pancreatic  juice.  It  was  shown 
long  ago  by  Williams  and  Martin  *  that  the  amylolytic  power 
of  pancreatic  extracts  is  doubled  by  the  addition  of  bile  or 
of  bile  salts.  Pawlow  has  stated  that  the  same  holds  good  of 
the  proteolytic  power  of  this  juice.  Most  important,  however, 
is  ihe  part  played  by  the  bile  in  the  digestion  and  absorption 

*  Proc.  Eoy.  Soc,  Vol.  XLV.,  p.  48  and  Vol.  XL VIII.,  p.  160,  1890. 


THE    BILE. 


117 


of  fats.  The  fat-splitting  action  of  pancreatic  juice  is  trebled  by 
the  addition  of  bile,  whether  boiled  or  unboiled.  This  quicken- 
ing action  of  the  bile  probably  depends,  like  its  function  in 
the  absorption  of  fats,  on  the  peculiar  physical  properties 
of  the  bile  salts,  with  those  of  the  lecithin  and  cholesterin, 
which  are  held  in  solution.  Not  only  does  such  a  solution 
diminish  the  surface  tension  between  watery  and  oily  fluids,  so 
promoting  the  closer  approach  by  the  lipase  of  the  pancreatic 
juice  to  the  fats  on  w4iich  it  is  to  act,  but  it  has  also  the 


/ 

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\   n   ^    '    '    I    ■    J    '     ^    I     I     '        -- ^-^  L   1   .    L  i.  i    1     Li-  1.-1. *• — 1 1 ^- 1- 1 :^ 1 i i-^™- 

iff^xufj  ' 

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__      , L             J iLUXX  .L^X_U_-l-i_J 4  l—l-A.    l-*-t_L_i_JU 

j_i_-i_  J— 

n 

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.,   i-  ■.-.   \  V  ,-,.,   1   >•,■,,>■,<   i  >'.■,»(  y  ■,■,,,■'.<  1   -  1  i-^.  \   \  )  )  \  \ii  \\)  \  \\\  \  '   \\  \  \\  W  < — ^  )  \\  \  ■■■ 

Fig.  11. — Effect  of  injection  of  secretin  on  the  flow  of  pancreatic  juice 
and  of  bile.  The  hnes  from  above  downwards  represent — (1)  Blood 
pressure  ;  (2)  drops  of  pancreatic  juice ;  (3)  drops  of  bile  ;  (4)  signal 
marking  moment  of  injection  of  secretin ;  (5)  time-marking  10" 
intervals. 


powder  of  dissolving  fatty  acids  and  soaps,  including  even  the 
insoluble  calcium  and  magnesium  soaps.  It  is  probable  that 
it  aids  also  in  holding  in  solution,  and  bringing  in  contact 
wdth  the  fat,  the  lipase  of  the  pancreatic  juice.  It  has  been 
shown  by  Nicloux*  that  the  lipase  contained  in  oily  seeds,  such 
as  those  of  the  castor  plant,  is  insoluble  in  water  but  soluble 
in  fatty  media.  The  dried  ferment  obtained  from  the  pan- 
creas in  many  cases  yields  no  lipase  to  water,  but  gives  a 
strongly  lipolytic  solution  when  extracted  with  glycerin.  The 
digestive  function  of  bile  therefore  lies  in  its  power  of  serving 
as  a  vehicle  for  the  suspension  and  solution  of  the  interacting 

*  V.  Proc.  Koy.  Soc,  Series  B,  Vol.  LXXVII.,  p  454. 


118  THE    PHYSIOLOGY    OF    DIGESTION. 

fats,  fatty  acids,  and   fat-splitting  ferment.     This   vehicular 
function  plays  an  important  part  in  the  absorption  of  fats. 
These  pass  through  the  striated  basilar  membrane  bounding 
the  intestinal  side  of  the  epithelium,  not,  as  has  been  formerly 
thought,  in   a  fine   state   of   suspension  (an   emulsion),  but 
dissolved  in  the  bile  in  the  form  of  fatty  acids  or  soaps  and 
glycerin.     On  the  arrival  of  these  products  of  digestion  in  the 
epithelial  cells,  a  process  of  resynthesis  is  set  up.     Droplets 
of  neutral  fat  make  their  appearance  in  the  cells,  whence  they 
are  passed  gradually  into  the  central  lacteal  villus  and  so  into 
the  lymphatics  of  the  mesentery  and  into  the  thoracic  duct. 
The  bile  salts  thus  released  from  their  function  as  carriers  are 
absorbed  by  the  blood  circulating  through  the  capillaries  of 
the  villi,  and  carried  by  the  portal  vein  to  the  liver.     Arrived 
here  they  are  once  more  taken  up  by  the  liver  cells  and  turned 
out  into  the  bile.     Owing  to  the  fact  of  their  ready  excretion 
by  the  liver  cells,  bile  salts  are  the  most  reliable  cholalogues 
with  which  we  are  acquainted.     By  this  circulation  of  bile 
between  liver  and  intestine,  the  synthetic  work  of  the  liver  in 
the  production  of  the  bile  salts  is  reduced  to  a  minimum,  and 
it  has  only  to  replace  such  of  the  bile  salts  as  undergo  destruc- 
tion in  the  alimentary  canal,  under  the  influence  of  micro- 
organisms, and  are  lost  to  the  organism  by  passing  out  in  the 
faeces  as  a  gummy  amorj)hous  substance,  known  as  dy  sly  sin. 
Further  investigation  is  still  wanted  as  to  the  exact  method 
in  which  secretin  acts  on  the  liver  cells,  and  especially  as  to 
whether  it  actually  excites  in  them  the  manufacture  of  fresh 
bile  salts,  or  whether  it  simply  hastens  the  excretion  of  such 
bile  salts  as  have  been  formed  by  the  spontaneous  activity  of 
the  liver  cells  or  have  arrived  at  them  after  absorption  from 
the  alimentary  canal.     Such  questions  can  only  be  decided 
by  studying  the  action  of  secretin  on  animals  possessing  a 
permanent  biliary  fistula. 


THE    BILE.  119 

From  the  fact  that  the  secretion  of  bile  runs  parallel  with 
that  of  pancreatic  juice,  and  is  excited  by  the  same 
mechanism,  we  should  expect  it  to  alter  with  variations  in 
the  diet.  The  secretion  of  bile  on  various  diets  has  been 
studied  by  Barbera.  He  finds  that,  whereas  the  secretion  of 
bile  is  greatest  on  a  meat  diet,  it  is  somewhat  less  on  a  diet 
of  fat,  and  is  insignificant  on  a  purely  carbohydrate  diet. 
That  is  to  say,  the  secretion  of  bile  is  greatest  on  those  diets, 
the  digestion  of  which  is  attended  by  the  passage  of  a  large 
amount  of  acid  chyme  or  of  oil  into  the  duodenum.  We  have 
seen  earlier  that  oil  is  almost  as  ejfficacious  as  acid  in  promot- 
ing the  production  of  secretin  in  the  living  duodenum,  the 
production  in  this  case  being  probably  determined  by  the 
formation  of  soap  from  the  oil,  and  the  direct  action  of  the 
soap  on  the  prosecretin  in  the  epithelial  cells  of  the  gut. 


LECTUKE   IX. 


THE    INTESTINAL   JUICE. 


We  have  seen  that  for  the  development  of  one  of  its  most 
important  properties,  namely,  that  of  proteolysis,  the  pan- 
creatic juice  is  dependent  on  the  co-operation  of  the  intestinal 
juice  or  succus  entericus.  Besides  this  activating  power  on  the 
pancreatic  juice,  the  intestinal  juice  has  numerous  other  func- 
tions to  discharge  in  the  digestion  of  the  food-stuffs.  Before 
discussing  its  actions  in  detail,  we  may  consider  the  conditions 
which  determine  its  secretion.  In  spite  of  the  great  similarity 
which  obtains  between  the  microscopic  structure  of  the  wall  of 
the  gut  at  different  levels  from  duodenum  to  ileo-colic  valve, 
functionally  there  are  many  differences  between  the  upper, 
middle,  and  lower  portions  of  the  gut.  Speaking  generally, 
we  may  say  that,  whereas  the  processes  of  secretion  are  best 
marked  in  the  upper  portions  of  the  gut,  the  processes  of 
absorption  predominate  in  the  lower  sections,  i.e.,  in  the  ileum. 
Much  of  the  divergence  in  the  statements,  which  have  been 
made  with  regard  to  the  factors  determining  secretion  and 
absorption  in  the  small  intestine,  is  due  to  the  failure  to 
appreciate  this  great  difference  between  the  activity  of  the 
mucous  membrane  at  various  levels.  The  processes  of  secre- 
tion in  the  small  intestine  may  be  studied  by  isolating  loops 
by  means  of  ligatures,  and  determining  the  amount  of  secretion 
formed  in  these  loops  in  the  course  of  a  few  hours'  experiment 
on  an  anaesthetised  animal.  Better  results,  however,  may  be 
obtained  by  establishing  permanent  fistulse.     These  fistulse  are 


THE    INTESTINAL    JUICE.  121 

of  two  kinds.  Thiry's  original  method  of  establishing  a 
fistula  consisted  in  cutting  out  a  loop  of  intestine,  and  restoring 
the  continuity  of  the  gut  by  suturing  the  two  ends  from  which 
the  loop  had  been  severed.  The  upper  end  of  the  loop  itself  is 
closed  and  the  lower  end  is  sutured  into  the  abdominal  wound. 
For  some  purposes  it  is  better  to  make  a  Thiry-Vella  fistula. 
In  this  case  the  continuity  of  the  gut  is  restored  as  in  the 
simple  Thiry  fistula,  but  both  ends  of  the  excised  loop  are  left 
open  and  brought  into  the  abdominal  wound.  In  such  a 
fistula  it  is  easy  to  introduce  substances  into  the  upper  end 
and  determine  the  flow  of  juice  from  the  lower  end,  the 
constant  emptying  of  the  loop  ])eing  provided  for  by  the 
peristaltic  contractions  of  its  muscular  coat. 

In  animals  with  intestinal  fistula,  a  number  of  different  con- 
ditions have  been  found  to  give  rise  to  a  flow  of  succus  entericus, 
and  so  far  no  qualitative  difference  has  been  recorded  between 
the  upper  and  lower  ends  of  the  gut.  A  condition,  which  will 
cause  a  free  flow  of  juice  from  a  fistula  high  up  in  the  intestine, 
will  generally  cause  a  scanty  flow  from  a  fistula  made  from 
the  ileum.  In  all  cases  it  is  found  that  a  flow  of  juice  is  pro- 
duced in  consequence  of  a  meal.  If  a  dog  with  a  fistula,  which 
has  been  starved  for  twenty-four  hours,  be  given  a  meal  of  meat, 
a  flow  of  juice  may  begin  within  the  next  ten  minutes.  The 
flow  remains  very  slight  for  about  two  hours  and  then  suddenly 
increases  in  amount  during  the  third  hour,  corresponding  thus 
very  nearly  to  the  flow  of  pancreatic  juice  excited  by  the  same 
means.  In  this  postprandial  secretion  of  juice  it  is  not  pro- 
bable that  the  nervous  system  takes  any  very  large  share, 
though  its  intervention  in  the  secretion  has  not  been  excluded 
by  direct  experiment.  There  are  certain  facts  which  seem 
indeed  to  f^peak  for  an  action  of  the  central  nervous  system  on 
the  processes  of  intestinal  secretion  ;  not  in  the  direction  of 
augmentation,  but  in  the  direction  of  inhibition  of  secretion. 


122  THE    PHYSIOLOGY    OF    DIGESTION. 

Thus  it  has  been  observed,  on  many  occasions,  that  extirpa- 
tion of  the  nerve  plexuses  of  the  abdomen  or  section  of  the 
splanchnic  nerves  causes  a  condition  of  diarrhoea,  which  may 
last  for  two  or  three  days.     This  condition  might  be  deter- 
mined, either  by  an  increased  motor  activity  of  the  gut,  or  by 
removal   of   inhibitory   impulses   normally    arriving    at    the 
intestinal  glands.      Such   a  view   receives  support   from   an 
experiment  first  performed  by  Moreau.     The  abdomen  of  a  dog 
is  opened  under  an  anaesthetic,  and  three  contiguous  loops  of 
small  intestine  are  separated  by  means  of  ligatures  from  the 
rest   of   the   gut.     The   middle  loop   is   then  denervated  by 
destruction  of  all  the  nerve  fibres  lying  on  its  blood  vessels,  as 
they  course  through  the  mesentery,  care  being  taken  not  to 
injure   the   blood   vessels   themselves.      The   loops  are  then 
replaced  in  the  abdomen  and  the  animal  left  from  four  to 
sixteen  hours.     On  killing  the  animal  at  the  end  of  this  time, 
it  is  often  found  that  the  middle  loop,  i.e.,  the  denervated  loop, 
is  distended  with  fluid  having  all  the  properties  of  ordinary 
intestinal  juice,  whereas  the  other  two  loops  are  empty.     A 
series    of    comparative    experiments   by   Mendel  *    and   by 
Falloise  f    have   shown  that  the  secretion  begins  about  four 
hours  after  the  operation,  increases  for  about  twelve  hours, 
and  then  rapidly  declines,  so  that  at  the  end  of  two  days  all 
three  loops  will  be  found  empty.     This  has  often  been  inter- 
preted as  due  to  the  removal  of  inhibitory  impulses  passing 
from   the   central    nervous    system   to    the    local    secretory 
mechanism,  and  we  have  no  direct  evidence  which  can  be 
adduced  against  such  a  view.     It  is  possible,  however,  that  the 
hyperaemia  of  the  gut,  which  is  produced  by  the  processes  of 
denervation,  may  be  sufficient  to  account  for  the  increased 
formation  of  intestinal  juice,  since  the  hyperaemia  will  tend  to 

*  Mendel,  Pfluger's  Archiv.,  Vol.  LXIII.,  p.  425,  1896. 

t  Falloise,  Archives  internat.  de  Physiol.,  Vol.  I.,  p.  261,  1904. 


THE    INTESTINAL   JUICE.  128 

pass  off  as  the  vessels  recover  a  local  tone,  just  as  we  have 
seen  happens  with  the  increased  secretion. 

It  is  not  possible  to  explain  the  flow  of  intestinal  juice, 
which  follows  a  meal,  by  any  assumption  of  nervous  impulses 
transmitted  through  the  local  nerve  plexuses  of  the  gut,  since 
these  have  been  divided  in  the  making  of  the  fistula.  If 
we  exclude  a  nervous  reflex  action  by  the  long  paths,  namely 
through  the  spinal  cord  and  the  sympathetic  or  vagus  nerves, 
the  flow  which  attends  the  passage  of  food  into  the  first 
part  of  the  duodenum  must  be  excited  by  the  formation  of  some 
chemical  messenger.  As  to  the  existence  of  such  a  chemical 
messenger  or  hormone  for  the  intestinal  secretion,  there  can 
be  no  doubt,  but  the  evidence  as  to  its  precise  nature  is  at 
present  conflicting.  It  is  stated  by  Pawlow  that  the  most 
effective  stimulus  to  the  flow  of  succus  entericus  is  the  presence 
of  pancreatic  juice  in  the  loop  of  gut.  In  the  few  experiments 
which  I  have  made  on  a  fistula  from  the  middle  of  the  small 
intestine,  I  have  not  observed  such  a  marked  stimulating 
effect  of  pancreatic  juice  on  intestinal  secretion  as  is  described 
by  Pawlow,  but  it  is  possible  that  the  effect  of  the  local 
introduction  of  pancreatic  juice  may  vary  with  the  location  of 
the  fistula.  No  evidence  has  yet  been  brought  forward  that 
injection  of  pancreatic  juice  into  the  blood  stream  will  cause 
any  flow  of  intestinal  juice.  Whatever,  therefore,  may  be  the 
local  effects  of  this  juice,  it  is  doubtful  whether  we  can  regard 
it  as  the  hormone,  whose  absorption  from  the  duodenum 
determines  the  postprandial  flow  of  juice  in  the  isolated  loop 
of  gut. 

We  have  already  seen  that  the  simultaneous  presence  in 
the  gut  of  the  two  juices,  bile  and  pancreatic  juice,  whose  co- 
operation is  necessary  for  the  full  manifestation  of  the  actions 
of  each,  is  ensured  l)y  the  presence  of  one  and  the  same 
chemical  messenger  for  the  arousing  of  both  secretions.    Since 


124  THE    PHYSIOLOGY    OF    DIGESTION. 

the  co-operation  of  succus  entericus  is  also  necessary  for  the 
intestinal  digestion,  we  might  anticipate  that  the  secretin, 
which  excites  both  bile  and  pancreatic  secretion,  would  also 
excite  a  secretion  of  succus  entericus.  That  this  is  true,  at 
any  rate  for  the  upper  segments  of  the  gut,  has  been  shown 
by  Delezenne  and  Frouin.  In  procuring  pancreatic  juice  by 
the  intravenous  injection  of  secretin,  it  is  always  found  that 
the  small  intestine  contains  a  considerable  quantity  of  fluid, 
presumably  intestinal  juice.  This  might  be  regarded  as  a 
secretion  excited  by  the  escape  of  a  small  amount  of  pancreatic 
juice  into  the  gut  along  the  second  pancreatic  duct,  which  is 
generally  left  unligatured  in  this  experiment.  The  two 
French  observers,  however,  have  shown  that  in  animals  pro- 
vided with  a  permanent  fistula  involving  the  duodenum  or  upper 
part  of  the  jejunum,  intravenous  injection  of  secretin  always 
causes  a  secretion  of  intestinal  juice.  In  the  upper  part  of 
the  gut,  therefore,  the  simultaneous  presence  of  the  three 
juices  necessary  for  comjDlete  duodenal  digestion  is  ensured 
by  one  and  the  same  mechanism,  namely,  by  the  simultaneous 
activity  of  the  secretin,  produced  in  the  intestinal  cells  by  the 
action  of  the  acid  chyme,  on  pancreas,  liver,  and  intestinal 
glands. 

Eecently  a  further  chemical  mechanism  for  the  arousing  of 
intestinal  secretion  has  been  described  by  Frouin.  According 
to  this  observer,  the  flow  of  juice  can  be  excited  by  intravenous 
injection  of  intestinal  juice  itself.  Since  this  juice  is  alkaline, 
and  does  not  produce  any  effect  on  the  pancreas,  it  must  be 
free  from  pancreatic  secretin.  It  would  seem,  therefore,  that 
the  flow  of  juice  in  the  upper  part  of  the  gut,  excited  by  the 
pancreatic  secretin,  causes  also  a  production  of  a  different 
secretin  or  hormone,  which  can  be  absorbed  from  the  lumen 
of  the  gut,  travel  by  the  blood  stream  to  other  segments  of  the 
small  intestine,  and  there  excite  a  secretion  in  preparation 


THE    INTESTINAL   JUICE.  125 

for  the  oncoming  food.     Further  experiments  are,  however, 
necessary  on  this  point. 

Besides  this  sensitiveness  to  chemical  stimulation,  the 
glands  of  the  small  intestine  can  be  excited  by  direct  mechani- 
cal stimulation  of  the  mucous  membrane.  The  easiest  method 
of  exciting  a  flow  of  intestinal  juice  from  a  permanent  fistula 
is  to  introduce  into  the  intestine  a  rubber  tube.  The  presence 
of  the  solid  object  in  the  gut  causes  a  secretion,  and  within  a 
few  minutes  drops  of  juice  can  be  obtained  from  the  free 
end  of  the  tube.  The  object  of  such  a  sensibility  to  mechani- 
cal stimuli  is  obvious ;  it  is  of  the  highest  importance  that  the 
onward  passage  of  any  solid  object,  especially  if  it  be  indiges- 
tible, shall  be  aided  by  the  further  secretion  of  juice  in  the 
portions  of  gut  which  are  immediately  stimulated.  This 
mechanical  stimulation  probably  acts  on  the  tubular  glands 
of  the  intestine  through  the  intermediation  of  the  local  nervous 
system,  the  plexus  of  Meissner.  It  is  stated  by  Pawlow  that 
a  juice  obtained  by  mechanical  stimulation  differs  from  that 
produced  by  the  introduction  of  pancreatic  juice  into  the  loop, 
in  containing  little  or  no  enterokinase.  Apparently  the  pan- 
creatic juice  excites  the  secretion  of  the  substance  which  m 
necessary  for  its  own  activation. 

CHARACTERS    OF    INTESTINAL   JUICE. 

The  intestinal  juice  obtained  from  a  permanent  fistula  has  a 
specific  gravity  of  about  1010.  It  is  generally  turbid  from 
the  presence  in  it  of  migrated  leucocytes  and  disintegrated 
epithelial  cells.  It  contains  about  1*5  per  cent,  total  solids^ 
of  which  '8  per  cent,  are  inorganic  and  consist  chiefly  of 
sodium  carbonate  and  sodium  chloride.  It  is  markedly 
alkaline  in  reaction,  but  less  so  than  the  pancreatic  juice. 
The  organic  matter,  besides  a  small  amount  of  serum  albumen 
and   serum   globulin,  includes  a  number  of  ferments,  all  of 


126  THE    PHYSIOLOGY    OF    DIGESTION. 

which  are  adapted  to  complete  the  processes  of  digestion  of 
the  food-stuffs  commenced  in  the  stomach  and  duodenum. 
Of  these  ferments  two  are  concerned  in  proteolysis.  Entero- 
kinase  we  have  already  studied  in  detail.  Possessing  no 
action  itself  on  proteids,  it  is  a  necessary  condition  for  the 
development  of  the  full  proteolytic  powers  of  the  pancreatic 
juice.  In  addition  to  this  ferment  another  ferment  has  been 
described  by  Cohnheim  under  the  name  '  erepsin.'  Erepsin 
or  some  similar  ferment  is  present  in  the  fresh  pancreatic 
juice  and  in  almost  all  tissues  of  the  body.  It  is  distin- 
guished by  the  fact  that,  although  it  has  no  power  of  digest- 
ing coagulated  proteid  or  gelatin,  and  only  slowly  dissolves 
caseinogen  and  fibrin,  it  has  a  rapid  hydrolytic  effect  on  the 
first  products  of  proteolysis,  converting  albumoses  and  pep- 
tones into  amino-  and  diamino-acids — their  ultimate  cleavage 
products. 

The  other  ferments  of  the  intestinal  juice  are  all  connected 
with  the  digestion  of  carbohydrates.  In  all  mammals  the 
intestinal  juice  is  found  to  contain  invertase,  which  trans- 
forms cane  sugar  into  glucose  and  laevulose  or  fructose, 
and  maltase  which  converts  maltose  into  glucose.  In  young 
mammals,  as  well  as  in  those  in  whom  the  milk  diet  is  con- 
tinued throughout  life,  the  intestinal  mucous  membrane  also 
contains  lactase,  i.e.,  a  ferment  converting  milk  sugar  into 
galactose  and  glucose.  Such  a  ferment  can  be  extracted  from  the 
mucous  membrane  of  all  young  animals,  but  may  be  very  slight 
or  even  absent  in  the  intestines  of  older  animals,  when  it  is  no 
longer  needed  for  the  ordinary  processes  of  nutrition.  By 
means  of  these  three  ferments,  coming  as  they  do  after  the 
digestion  of  the  starches  by  the  amylase  of  the  saliva  and  pan- 
•creatic  juice,  it  is  provided  that  all  the  carbohydrate  food  of 
the  animal  is  transformed  into  a  hexose,  in  which  form  alone 
carbohydrate  can  be  taken  up  and  assimilated  by  the  cells  of 


THE    INTESTINAL    JUICE.  127 

the  body.  If  a  disaccharide,  such  as  cane  sugar  or  lactose,  be 
injected  into  the  circulation,  it  is  excreted  unchanged  in  the 
urine.  On  the  other  hand  the  injection  of  moderate  quantities 
of  the  hexoses,  glucose,  fructose,  or  galactose  into  the  circula- 
tion does  not  lead  to  the  appearance  of  the  sugars  in  the  urine, 
but  causes  an  increased  formation  of  glycogen  by  the  liver. 
The  seat  of  origin  of  these  various  ferments  has  been  the 
subject  of  special  investigation  by  Falloise.*  Bayliss  and  I 
had  already  shown  that  secretin  can  be  obtained  from  the 
whole  thickness  of  the  mucous  membrane,  and  is  probably 
therefore  contained  in  the  form  of  prosecretin  in  the  epithelial 
cells  covering  the  villi  as  well  as  in  those  lining  the  follicles 
of  Lieberkuhn.  On  the  other  hand  a  superficial  scraping  of 
the  mucous  membrane,  which  removes  only  the  epithelial  cells 
covering  the  villi  with  the  adherent  mucus  and  intestinal  secre- 
tion, gives  a  much  more  active  solution  of  enterokinase  than 
the  deeper  scraping  of  mucous  membrane.  This  result  is 
confirmed  by  Falloise,  who  therefore  places  the  seat  of  pro- 
duction of  enterokinase  in  the  cells  covering  the  intestinal 
villi.  The  most  active  solutions  of  enterokinase  are,  however, 
to  be  obtained  from  the  fluid  found  in  the  cavity  of  the 
intestine  after  the  injection  of  secretin.  We  are  therefore 
inclined  to  believe  that  enterokinase  is  not  present  as  such 
in  the  epithelial  cells,  but  is  first  produced  in  the  process 
of  secretion  and  formation  of  the  intestinal  juice.  The  other 
ferments,  namely  erepsin,  maltase,  invertase,  and  lactase,  pro- 
bably pre-exist  as  such  in  the  epithelial  cells,  especially  in  those 
lining  the  tubular  glands  of  the  gut,  since  pounded  mucous 
membrane  in  water  yields  a  solution  of  these  ferments  which 
is  generally  more  powerful  in  its  action  than  the  succus 
entericus  itself.  So  great  is  the  difference,  in  fact,  that  many 
physiologists  have  suggested  that  the  chief  action  of  these 
*  Archives  internat.  de  Physiol,  Vol.  II.,  p.  299,  1905. 


128  THE    PHYSIOLOGY    OF    DIGESTION. 

ferments  occurs,  not  in  the  lumen  of  the  gut,  but  in  the  pass- 
age of  the  food-stuffs  through  the  epitheHal  cells  of  the  small 
intestine  on  their  way  to  the  blood  vessels. 

As  the  result  of  all  these  changes,  the  three  classes  of  food- 
stuffs are  reduced  to  a  soluble  condition,  and  in  solution  are 
taken  up  by  the  cells  lining  the  intestine.  In  the  case  of  the 
fats,  the  greater  part  are  at  once  resynthesised  into  insoluble 
neutral  fats  in  the  cells  themselves,  and  passed  on  in  this  form 
by  the  lacteals  and  lymphatic  system  into  the  blood  stream. 
So  far  as  experimental  evidence  goes,  the  sugars  and  disintegra- 
tion products  of  the  proteids  pass  directly  into  the  blood  stream, 
by  which  they  are  conveyed  to  the  liver  and  other  organs  of 
the  body,  where  they  are  either  stored  up  or  utilised  in 
furnishing  the  energy  required  for  the  discharge  of  the  bodily 
functions.  Only  to  a  small  extent  are  they  required  for  the 
building  up  of  the  tissues  in  replacement  of  loss  by  injury  or 
local  old  age  and  death.  The  main  function  of  the  alimen- 
tary tract  is,  therefore,  the  presentation  to  the  tissues  of  the 
body  of  the  food-stuffs  in  a  form  in  which  they  are  directly 
assimilable. 


LECTUEE    X. 

THE    MOVEMENTS  OF    THE    ALIMENTARY   TRACT. 

An  essential  part  in  the  digestive  act  is  played  by  the  con- 
tinual movements,  by  means  of  which  the  food  is  intimately 
mixed  with  the  digestive  juices  and  gradually  passed  on  from 
one  segment  of  the  canal  to  the  next.  By  these  movements 
the  organism  provides  for :  (1)  the  preparation  of  the  food 
for  digestion  by  reducing  it  to  a  condition  of  fine  sub- division 
by  means  of  the  movements  of  mastication  ;  (2)  the  intimate 
mixing  of  the  food  with  the  digestive  juices,  so  as  to  allow  of 
these  coming  in  contact  with  every  particle ;  (3)  the  propul- 
sion of  the  food  from  one  cavit}-  of  the  canal  to  the  next  so 
soon  as  the  processes  of  digestion  in  the  first  cavity  have  been 
completed ;  and  (4)  finally  the  rejection  and  expulsion  from 
the  body  of  the  undigestible  portions  of  the  food-stufis,  mixed 
with  the  products  of  excretion  of  the  wall  of  the  alimentary 
canal  itself. 

Although  the  researches  on  the  movements  of  the  alimentary 
canal  date  from  the  very  beginning  of  physiology,  it  is  only 
within  the  last  ten  years  that  the  enormous  mass  of  facts  and 
observations,  which  have  been  made,  have  been  reduced  to 
an  orderly  whole,  so  that  we  may  form  a  conception  of  the 
course  of  events  concerned  in  the  movements  of  the  food,  from 
the  time  that  it  enters  the  mouth  to  the  rejection  of  the 
undigested  portions  in  the  faeces.  In  the  case  of  the  secretory 
mechanism  we  have  seen  that,  whereas  the  first  parts  of  the 
alimentary  canal  are  under  the  direct  control  of  the  central 

P.D.  K 


130  THE    PHYSIOLOGY    OF    DIGESTION. 

nervous  system,  this  control  gets  less  and  less  with  the  onward 
progress  of  the  food ;  and  that,  in  the  duodenum  and  small 
intestine,  the  mechanism  for  evoking  the  secretion  of  the 
digestive  juices,  at  the  exact  time  and  place  where  they  are 
required,  is  local  or  chemical,  and  occurs  in  the  entire  absence 
of  any  connection  with  the  central  nervous  system.  In  the 
same  way  the  motor  reactions,  which  affect  the  beginning  of  the 
canal,  are  subject  to  the  central  nervous  system.  This  direct 
control  is  also  manifested  in  the  reactions  of  the  lowest  por- 
tions of  the  gut,  which  are  concerned  in  the  act  of  defsecation. 
The  middle  of  the  alimentary  canal  however,  although 
capable  of  being  affected  by  the  central  nervous  system  through 
ihe  splanchnic  and  vagus  nerves,  depends  for  the  greater  part 
of  its  activity  on  a  nervous  mechanism  situated  in  the  wall  of 
the  gut  itself.  The  mechanism  is  apparently  in  all  cases 
nervous,  and  we  have,  at  present,  no  evidence  of  motor 
reactions  being  evoked  by  the  circulation  in  the  blood  of 
chemical  substances  or  hormones.*  There  must  naturally 
be  a  wide  variation  in  the  details  of  the  motor  reactions  of  the 
alimentary  canal,  according  to  the  nature  of  the  food-stuffs 
chiefly  made  use  of  by  the  animal;  and  we  find  great 
differences  in  this  respect,  as  in  the  anatomy  of  the  canal, 
between  a  carnivorous  animal  such  as  the  dog  and  a  herbi- 
vorous animal  such  as  the  rabbit.  In  the  following  account  I 
shall  deal  chiefly  with  those  facts  which,  though  determined  by 
experiments  on  animals  of  both  classes,  can  be  directly 
applied  to  the  movements  of  the  alimentary  tract  in  man. 
After  the  food  has  been  reduced  by  movements  of  the  jaw, 

*  Apart,  that  is  to  say,  from  any  co-operation  on  the  part  of  nervous 
structures.  Adrenalin,  the  hormone  manufactured  by  the  suprarenal 
bodies,  seems  to  be  necessary  for  the  normal  display  of  the  functions  of 
the  sympathetic  system,  and  its  motor  or  inhibitory  effects  on  the  gut  are 
produced  through  this  system. 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TRACT.  131 

cheeks,  and  tongue  to  a  state  of  fine  pulp,  it  is  collected  by 
movements  of  the  tongue  into  a  bolus.  This  bolus  is  then 
rapidly  thrust  by  movements  of  the  tongue  muscles  back  into 
the  upper  part  of  the  oesophagus,  its  passage  over  the  region 
of  the  pharynx  common  to  the  purposes  of  alimentation  and 
respiration  being  effected  rapidly,  so  as  to  interfere  as  little  as 
possible  with  the  respiratory  movements.  The  oesophagus  is 
a  muscular  tube  lined  internally  with  mucous  membrane, 
which  is  constantly  moistened  with  mucus  secreted  by 
numerous  glands.  The  muscular  coat  consists  of  two  layers, 
longitudinal  fibres  externally  and  circular  fibres  internally. 
In  the  upper  part  of  the  oesophagus  both  these  layers  are 
composed  of  voluntary  striated  muscle.  In  the  lower  third  of 
the  oesophagus  the  muscle  is  entirely  of  the  unstriated  variety, 
and  in  the  middle  part  there  is  a  gradual  transition  between 
these  two  types.  The  food,  on  arriving  at  the  upper  part  of 
the  tube,  is  passed  rapidly  down  to  the  lower  end  and  through 
the  cardiac  orifice  into  the  stomach  by  means  of  a  peristaltic 
contraction. 

As  this  form  of  contraction  plays  a  great  part  in  the  onward 
movement  of  food  in  all  the  tubular  portions  of  the  alimentary 
canal,  it  may  be  well  to  define  here  more  explicitly  what  we 
mean  by  the  term  '  peristalsis.'  A  peristaltic  contraction  is 
a  co-ordinated  act,  comparable  in  many  respects  with  the  co- 
ordinated movement  of  extension  or  flexion  which  occurs  in 
a  limb  as  a  result  of  an  appropriate  sensory  stimulus.  Each 
such  co-ordinated  movement  involves,  as  has  been  so  ably 
demonstrated  by  Sherrington,  two  opposed  processes — excita- 
tion and  inhibition.  If,  for  instance,  the  leg  be  flexed  in 
response  to  a  painful  stimulus  applied  to  the  sole  of  the  foot, 
this  flexion  includes  contraction  of  the  flexor  muscles  and  inhibi- 
tion of  the  extensor  muscles.  If  the  flexor  muscles  be  divided, 
it  is  still  possible  to  show  that  the  extensor  muscles  undergo 

K    2 


132  THE    PHYSIOLOGY    OF    DIGESTION. 

a  lengthening  as  the  result  of  the  application  of  the  stimulus. 
In  the  same  way  a  movement  of  extension  of  the  leg,  in 
response  to  a  particular  tactile  stimulus  applied  to  the  ball  of 
the  foot,  can  be  properly  carried  out  only  by  a  two-fold  dis- 
charge causing  inhibition  of  the  flexor  muscles,  and  contraction 
of  the  extensor  muscles.  The  uncoordinated  spasms  which 
distinguish  strychnine  poisoning  are  due  to  the  abolition  of 
the  inhibitoiy  part  of  each  reflex  and  its  conversion  into  a 
contractile  reaction,  so  that  antagonistic  muscles  are  set  into 
contraction  by  one  and  the  same  sensoiy  stimulus.  The 
physiological  purpose  of  a  j)ei'istaltic  contraction  is  the  pro- 
pulsion of  a  solid  or  semi- solid  object  along  a  tube.  A  simple 
contraction  of  the  tube,  even  if  propagated  along  its  walls, 
would  probably  pass  over  the  object,  squeezing  it  in  its  course 
but  not  effecting  an  onward  movement.  In  order  that  the 
object  or  bolus  may  be  moved  from  one  end  of  the  tube  to  the 
other,  it  is  necessary  that  a  process  of  contraction  of  the 
muscle  behind  it  should  be  accompanied  with  a  process  of 
relaxation  of  the  muscular  walls  of  the  tube  in  front  of  it. 
This  is  the  distinguishing  feature  of  a  peristaltic  contraction — 
a  process  of  contraction  behind  the  object,  and  a  process  of 
inhibition  and  relaxation  in  front  of  the  object.  Such  a 
double  process  can  be  effected  only  by  a  co-ordinating  centre. 
In  the  case  of  the  oesophagus  this  co-ordinating  centre  is 
situated  in  the  medulla,  and  the  orderly  progression  of  the 
peristaltic  wave  of  inhibition  jdus  contraction  along  the  walls 
of  the  tube  is  dependent  on  the  integrity  of  the  branches  of  the 
vagus  nerve,  by  which  the  medullary  centre  is  united  to  the 
gullet.  Division  of  these  nerves  destroys  the  power  of  swallow- 
ing. If  food  be  thrust  by  the  movements  of  the  tongue  into  the 
upper  part  of  the  oesophagus,  this  latter  may  become  filled  up 
with  food.  The  food  cannot  pass  into  the  stomach  on  account 
of  the  absence  of    the  one  definite  factor  in  the  peristaltic 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TPvACT.  133 

contraction,  namely  the  inhibition  in  front  of  the  bohis,  an 
inhibition  which  involves  also  the  cardiac  sphincter  of  the 
stomach.  It  seems  that,  under  normal  conditions,  a  stimulus 
applied  to  the  root  of  the  tongue  or  back  of  the  pharynx  and 
travelling  by  the  superior  laryngeal  nerves  to  the  vagus  centre 
in  the  medulla,  causes  a  fusillade  discharge  from  the  centre 
along  the  successive  fibres  of  the  vagus,  an  inhibitory  discharge 
preceding  in  each  case  the  motor  discharge. 

In  man  the  peristaltic  wave  takes  about  five  to  six  seconds 
to  pass  from  the  level  of  the  glottis  to  the  stomach,  the 
passage  being- rapid  in  the  upper  third,  in  the  region  of  the 
striated  muscle,  and  gradually  becoming  slower  as  the  striated 
muscle  gives  place  to  involuntary  muscle.  When  a  series  of 
swallowing  movements  are  carried  out,  the  lower  end  of  the 
(esophagus  remains  in  a  state  of  inhibition,  and  we  have 
simply  a  series  of  annular  constrictions  passing  down  the 
oesophagus  behind  each  food  bolus.  The  arrival  of  each  bolus 
in  the  stomach  can  be  detected  by  auscultating  the  back  of  a 
patient  over  the  region  of  the  cardiac  orifice.  A  gurgling 
sound  is  heard  each  time  the  food  passes  into  the  stomach. 

MOVEMENTS    OF    THE    STOMACH. 

When  a  meal  is  taken  the  inhibition,  which  precedes  the 
passage  of  each  bolus,  spreads  to  the  whole  stomach  wall,  so 
that  any  movements,  which  have  been  present  before  the  meal, 
come  to  an  end,  and  the  stomach  is  in  a  relaxed  and  passive 
condition  ready  to  receive  the  food  passing  to  it  from  the 
mouth.  The  food  passes  into  the  large  fundus  of  the  stomach 
and  accumulates  there  to  form  one  mass.  The  stomach 
remains  passive  for  some  time  after  the  beginning  of  a  meal, 
and  it  is  not  until  twenty  to  thirty  minutes  later  that  the 
first  movements  make  their  appearance.  Secretion  of  gastric 
juice    commences    even   while    the    food   is-  in  the   mouth. 


134  THE    PHYSIOLOGY    OF    DIGESTION. 

The  acid  juice  cannot,  however,  penetrate  the  great  mass  of 
food  which  is  lying  in  the  fundus,  and  in  the  interior  of  this 
mass  sahvary  digestion  can  go  on  from  thirty  minutes  to  one 
and  a  half  hours  after  the  food  has  been  swallowed.  A  very 
considerable  portion  therefore  of  the  salivary  digestion  occurs 
in  the  stomach  itself.  For  the  understanding  of  the  sub- 
sequent movements  of  the  gastric  wall,  it  is  important  to 
remember  its  functional  division  into  two  parts,  namely, 
fundus  and  pyloric  end  or  antrum.  Although  the  dead 
stomach  appears  to  form  one  sac,  observation  of  a  stomach, 
recently  removed  from  the  living  animal  and  placed  in  warm 
salt  solution,  shows  distinctly  this  division  into  two  parts, 
namely,  a  tubular  part  at  the  pyloric  end  and  a  bag-like 
portion,  forming  four -fifths  of  the  stomach,  at  the  cardiac  end. 
The  division  between  the  two  is  marked  by  what  has  been 
called  the  '  transverse  band '  of  the  stomach,  a  region  where 
there  is  almost  always  contraction  of  the  circular  muscle 
fibres.  So  marked  is  this  in  the  living  stomach  that  one 
would  expect  on  dissection  to  find  evidence  of  sphincter-like 
thickenings  at  this  point.  It  is,  however,  a  physiological  and 
not  an  anatomical  condition. 

The  movements  of  the  stomach  can  be  best  studied  by 
Cannon's  method,  that  is,  by  direct  observation  of  the  move- 
ments in  a  living  unansesthetised  animal,  by  means  of  the 
Rontgen  rays.  In  order  to  make  the  shape  of  the  stomach 
visible,  the  food — bread  and  milk — is  mixed  with  a  quantity 
of  bismuth  subnitrate.  The  presence  of  this  salt  does  not 
interfere  with  the  j)rocesses  of  digestion,  but  renders  the 
gastric  contents  opaque  to  the  Rontgen  rays.  On  examining 
by  this  means  the  stomach  of  a  cat,  wHich  has  just  taken  a 
meal,  the  whole  of  the  food  is  seen  to  be  lying  in  the  fundus. 
It  is  marked  off  by  a  strong  constriction  of  the  transverse 
band  from  the  antrum.     In  about  twenty  to  thirty  minutes, 


THE  move:\ients  of  the  alimentary  tract.  135 

faint  waves  of  contraction  begin  a  little  to  the  cardiac  side  of 
the  transverse  band  and  travel  slowly  towards  the  pylorus. 
These  waves  succeed  one  another,  so  that  the  pyloric  part 
of  the  stomach  may  present  a  series  of  constrictions.  The 
effect  of  these  waves  is  to  force  the  food,  which  has  been 
digested  by  the  gastric  juice  and  detached  from  the  surface  of 
the  mass  of  food  in  the  fundus,  towards  the  pylorus.  The 
pylorus  remaining  closed,  the  food  cannot  escape,  and  there- 
fore is  squeezed  back,  forming  an  axial  reflux  stream  towards 
the  cardiac  end.  These  contractions  last  throughout  the 
whole  period  of  gastric  digestion  and  become  more  marked  as 
digestion  proceeds.  Their  effect  is  to  bring  the  whole  of  the 
food  in  close  contact  with  every  particle  of  j^yloric  mucous 
membrane,  and  to  cause  a  thorough  mixture  of  food  and 
gastric  juice.  At  varying  periods  after  a  meal,  according  to 
the  nature  of  the  food  taken,  the  arrival  of  one  of  these  waves 
of  contraction  at  the  j)ylorus  causes  a  relaxation  of  its  orifice, 
and  a  few  cubic  centimetres  of  gastric  contents  are  squirted 
into  the  first  part  of  the  duodenum.  While  these  movements 
of  the  pyloric  mill  are  going  on,  the  cardiac  portion  of  the 
stomach  is  exercising  a  steady  pressure  on  its  contents,  in 
consequence  of  a  tonic  contraction  of  its  muscular  wall,  so 
that  each  successive  portion  of  the  food  mass,  which  is 
loosened  by  the  digestive  action  of  the  gastric  juice,  is  forced 
on  into  the  pyloric  mill.  As  digestion  proceeds,  the  opening 
of  the  pylorus  becomes  more  frequent.  The  stomach  empties 
itself  more  and  more,  until  finally  the  whole  of  the  viscus  has 
the  shape  of  a  curved  tube.  At  the  very  end  of  digestion,  the 
pylorus  may  open  to  allow  the  passage  even  of  undigested 
morsels  of  food. 

These  movements  of  the  two  portions  of  the  stomach  may 
be  observed  also  on  anaesthetised  animals,  and  even  on  a 
stomach   which   has   been  excised   and    placed  in   warm   salt 


136  THE    PHYSIOLOGY    OF    DIGESTION. 

solution.  They  must  therefore  have  their  origin  in  the  walls 
of  the  stomach  itself.  Although  the  co-ordination  between 
the  two  parts  of  the  stomach,  between  the  tonic  contraction  of 
the  fundus  and  the  rhythmic  contractions  of  the  antrum,  may 
be  carried  out  by  the  local  nervous  system — Auerbach's  plexus 
— situated  between  the  layers  of  the  muscular  coat,  it  is  pro- 
bable that  the  advancing  waves  of  contraction  observed  in  the 
antrum  are  myogenic,  i.e.,  directly  originated  in  and  deter- 
mined by  the  muscle  fibres  themselves.  Although  we  have 
no  direct  evidence  that  these  movements  persist  after  throwing 
the  local  nervous  system  out  of  action,  it  is  evident  that  they 
do  not  partake  of  the  nature  of  a  true  peristalsis,  since  they 
are  not  preceded  by  a  wave  of  relaxation.  The  opening  of  the 
p^dorus,  on  the  other  hand,  which  occurs  at  increasingly 
frequent  intervals  at  the  end  of  a  wave,  must  be  ascribed  to  a 
nervous  mechanism.  The  local  mechanism  probably  plays 
the  greater  part  in  this  act  of  relaxation,  though  there  is  no 
doubt  that  the  normal  emptying  of  the  stomach  is  also  largely 
dependent  on  the  integrity  of  the  connection  of  this  viscus 
with  the  central  nervous  system.  If  both  vagus  nerves  be 
divided  in  a  dog,  below  the  point  at  which  they  give  off  their 
branches  to  the  lungs  and  heart,  it  is  found  that  a  large 
amount  of  food  remains  in  the  stomach  in  an  undigested 
condition.  The  secretion  of  gastric  juice  is  deficient,  the 
movements  of  the  stomach  are  also  deficient,  and  the  opening 
of  the  pylorus  is  not  easily  carried  out.  Such  dogs,  therefore, 
tend  to  die  of  sapraemia,  being  poisoned  by  the  absorption  of 
products  of  putrefaction  from  the  gastric  contents.  Pawlow 
has  shown  that  animals  can  be  kept  alive  for  months  after 
division  of  both  vagi,  if  a  gastric  fistula  be  made,  the  animals 
be  carefully  fed,  and  care  be  taken  to  wash  out  adherent  non- 
digested  portions  of  food  from  the  stomach. 

The  opening  of  the  pylorus  depends  not  only  on  intragastric 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TRACT.  137 

events  but  also  on  the  condition  of  the  duodenum.  It  has 
been  shown  by  Serdjukow*  that  the  pylorus  remains  firmly 
closed  so  long  as  the  contents  of  the  duodenum  are  acid.  If 
alkaline  fluid  be  introduced  into  the  stomach,  this  is  rapidly 
passed  into  the  duodenum.  If,  however,  some  acid  be  intro- 
duced at  the  same  time  into  the  duodenum  by  means  of  a 
duodenal  fistula,  the  pylorus  remains  firmly  closed,  and  no 
fluid  passes  into  the  duodenum  until  the  acid,  which  was 
placed  there,  has  been  neutralised  by  the  secretion  of  pan- 
creatic juice  and  succus  entericus.  We  have  therefore,  in  the 
walls  of  the  alimentary  canal,  a  local  nervous  mechanism 
for  the  movements  of  the  pyloric  sphincter.  This  may  be 
played  upon  b}-  impulses  starting  either  in  the  stomach  or  in 
the  duodenum,  probably  by  the  contact  of  acid  with  the  mucous 
membrane.  Increasing  acidity  on  the  side  of  the  stomach 
causes  relaxation  of  the  orifice,  whereas  acidity  on  the  duodenal 
side  causes  contraction  of  the  pyloric  sphincter.  The  exact 
parts  played  in  this  mechanism  by  the  local  system  and  by 
the  central  nervous  system  respectively  have  not  yet  been 
thoroughly  made  out. 

MOVEMENTS    OF    THE    INTESTINES. 

The  movements  of  the  intestines  can  be  investigated  either 
by  observation  of  the  exposed  gut,  or  by  the  shadow  method 
introduced  by  Cannon,  in  which  the  nature  of  the  movements 
is  judged  from  the  shadows  of  food  containing  bismuth  which 
are  thrown  on  a  sensitive  screen  by  means  of  tbe  Eontgen 
rays.  These  movements  have  been  the  subject  of  experimental 
investigation  for  many  years,  but  with  ver}^  varying  results. 
The  great  discrepancy,  which  obtained  between  the  statements 
of  earlier  observers,  is  due  to  the  fact  that  they  failed  to  exclude 

■^  Quoted  by  Pawlow,  loc.  cit.,  p.  164. 


138  THE    PHYSIOLOGY    OF    DIGESTION. 

the  many  disturbing  impulses  which  can  play  on  any  segment 
of  the  gut,  either  reflexly  through  the  central  nervous  system, 
or  from  other  parts  of  the  alimentary  canal  itself  through  the 
local  nervous  system.  In  order  to  observe  the  normal  move- 
ments of  the  gut,  it  is  necessary  to  exclude  the  disturbing 
influences  due  to  reflexes  through  the  central  nervous  system, 
either  by  extirpation  of  the  whole  of  the  nerve  plexuses 
in  the  abdomen,  or  by  division  of  the  splanchnic  nerves,  or 
by  destruction  of  the  lower  part  of  the  spinal  cord  from  about 
the  middle  dorsal  region.  If  the  abdomen  of  an  animal,  which 
has  been  treated  in  this  way,  be  opened  in  a  bath  of  warm 
normal  salt  solution,  so  as  to  exclude  the  disturbing  influence 
of  drying  and  cooling  of  the  gut,  the  small  intestine  will  be 
seen  to  present  two  kinds  of  movements.  In  the  first  place, 
all  the  coils  of  gut  undergo  swaying  movements  from  side  to 
side — the  so-called  pendular  movements.  Careful  observation 
of  any  coil  will  show  that  these  movements  are  attended  with 
slight  waves  of  contraction  passing  rapidly  over  the  surface. 
If  a  rubber  balloon,  filled  with  air  and  connected  with  a  tam- 
bour, be  inserted  into  any  part  of  the  gut,  it  will  show  the 
existence  of  rhythmic  contractions  of  the  circular  muscle 
repeated  from  twelve  to  thirteen  times  per  minute.  By  means 
of  a  special  piece  of  apparatus  (the  '  enterograph '),  it  is  possible 
without  opening  the  gut  to  record  the  movements  of  either 
circular  or  longitudinal  muscular  coats ;  and  it  is  then  found 
that  both  coats  present  rhythmic  contractions  at  the  same 
rate,  the  two  coats  at  any  point  contracting  synchronously. 
When  the  contractions  are  recorded  by  means  of  a  balloon, 
the  constriction  which  accompanies  each  contraction  is  seen 
to  be  most  marked  at  the  middle  of  the  balloon,  i.e.,  at  the 
point  of  greatest  tension,  and  the  amplitude  of  the  contrac- 
tions is  augmented  by  increasing  the  tension  on  the  walls 
of  the  gut.     These  movements  are  unaffected  I)y  the  direct 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TRACT.  139 

application  of  drugs  such  as  nicotine  or  cocaine,  which  we 
might  expect  to  paral^^se  any  local  nervous  structures  in  the 
wall  of  the  gut.  Bayliss  and  I  therefore  concluded  that  these 
rhythmic  contractions  were  myogenic,*  that  they  were  pro- 
pagated from  muscle  fibre  to  muscle  fibre,  and  that  they 
coursed  down  the  gut  at  the  rate  of  about  5  cm.  per  second. 
Since,  how^ever,  they  may  apparently  arise  at  any  portion  of 
the  gut  which  is  subject  to  any  special  tension,  it  is  not  easy 
to  be  certain  that  a  contraction  recorded  at  any  point  is  really 
propagated  from,  a  point  two  or  three  inches  higher  up.  We 
suggested  that  the  action  of  these  contractions  was  to  cause  a 
thorough  mixing  of  the  contents  of  the  gut  with  the  digestive 
fluids. 

The  exact  value  of  these  movements  for  the  digestive  pro- 
cesses is  shown  very  clearly  when  they  are  observed  by 
Cannon's  method.!  On  examining  under  the  Eontgen  rays 
the  intestines  of  a  cat,  which  has  taken  a  large  meal  of  bread 
and  milk  mixed  with  bismuth  some  hours  previously,  a  length 
of  gut  may  be  seen,  in  which  the  food  contents  form  a  con- 
tinuous column.  Suddenly  movements  occur  in  this  column, 
which  is  split  into  a  number  of  equal  segments.  Within  a 
few  seconds  each  of  these  segments  is  halved,  the  correspond- 
ing halves  of  adjacent  segments  uniting.     Again  contractions 


*  Magnus  has  shown  that  it  is  possible  to  pull  off  strips  of  the  longi- 
tudinal (outer)  coat  of  muscle  fibres  from  the  small  intestine.  Such 
strips,  if  they  contain  Auerbach's  plexus,  will  contract  rhythmically  if 
kept  in  warm  oxygenated  Einger's  fluid.  If,  however,  the  plexus  has 
been  left  behind  in  strippmg  off  the  nmscle,  no  rhythmic  contractions  are 
to  be  observed,  ahhough  contraction  can  still  be  excited  by  artificial 
stimulation.  jVIagnus  concludes  that  even  the  rhythmic  '  pendular  '  con- 
tractions depend  for  their  occurrence  on  the  integrity  of  the  connection 
between  local  ganglionic  centres  and  muscle  fibres,  and  cannot  therefore 
be  strictly-  regarded  as  myogenic  {Pfiiigefs  ArcJiir.,  CII.,  p.  349,  1904). 

t  Cannon,  Anier.  Journ.  of  Physiol.,  Vol.  YI.  p.  251,  1901. 


140 


THE    PHYSIOLOGY    OF    DIGESTION. 


recur  in  the  original  positions,  dividing  the  newly-formed 
segments  of  contents  and  re-forming  the  segments  in  the 
same  position  as  they  had  at  first  (Fig.  12).  If  the  con- 
traction is  a  continuous  propagated  wave,  it  is  evidently 
reinforced  at  regular  intervals  down  the  gut,  so  as  to  divide 
the  column  of  food  into  a  number  of  spherical  or  oval  segments. 
In  this  way  the  points  of  greatest  tension  immediately  become 
the  points  which  are  midway  between  the   spots  where  the 


Fig.  12.  Diagram  (from  Camion)  showing  the 
appearance  of  a  length  of  gut  filled  with  food  contents. 
Each  of  the  portions,  into  which  the  contents  are 
divided,  are  segmented  by  subsequent  contractions  at 
two  points  (shown  by  dotted  lines)  and  then  return  to 
their  first  condition.  The  arrows  indicate  the  rela- 
tion of  the  pieces  to  the  portions  they  subsequently 
form. 

first  contractions  were  most  pronounced.  The  second  con- 
tractions, therefore,  start  at  these  points  of  greatest  tension, 
and  divide  the  first  formed  segments  into  two  parts,  which 
join  with  the  corresponding  halves  of  the  neighbouring 
segments.  In  this  way  every  particle  of  food  is  brought 
successively  into  intimate  contact  with  the  intestinal  wall. 
These  movements  have  not  a  translatory  efiect,  and  a  column 
of  food  divided  up  in  this  way  may  remain  at  the  same  level 
in  the  gut  for  a  considerable  time. 

The  onward  progress  of  the  food  is  caused  by  a  true  peri- 
staltic contraction,  i.e.,  one  which  involves  contraction  of  the 


THE    MOA'EMENTS    OF    THE    ALIMENTARY    TRACT.  141 

gut  above  the  food  mass  and  relaxation  of  the  gut  below.  If 
a  balloon  be  inserted  in  the  lumen  of  the  exposed  gut,  it  will 
be  found  that  pinching  the  gut  above  the  balloon  causes  an 
immediate  relaxation  of  the  muscular  wall  in  the  neighbour- 
hood of  the  balloon.  This  inhibitory  influence  of  the  local 
stimulus  may  extend  as  much  as  two  feet  down  the  intestine 
towards  the  ileo-caecal  valve.      On  the  other  hand,  pinching 


Fig.  13.  Ehj'thmic  contractions  of  the  wall  of  the  small  intestine  (dog) 
recorded  by  inserting  a  rubber  balloon  into  the  lumen  of  the  gut,  and 
connectmg  it  by  a  tube  with  a  piston  recorder.  At  the  signal  (1),  the 
intestine  was  gently  pinched  one  inch  above  the  balloon.  The  effect  was 
immediate  and  lastmg  inhibition.  At  (2)  and  (3)  the  intestine  was 
pinched  half  an  inch  below  the  balloon  with  the  result  of  causing  in  each 
case  increased  contractions  at  the  level  of  the  balloon.  (Baj'liss  and 
Starling.) 

the  gut  half  an  inch  below  the  situation  of  the  balloon  causes 
a  strong  continued  contraction  to  occur  at  the  balloon  itself 
(Fig.  13).  We  see,  therefore,  that  stimulation  at  any  portion  of 
the  gut  causes  contraction  above  the  point  of  stimulus  and 
relaxation  below  the  point  of  stimulus  (the  '  law  of  the  in- 
testines ').  The  same  effect  is  produced  by  introduction  of  a 
bolus  of  food,  especially  if  it  be  large  or  have  a  direct  irritat- 
ing effect  on  the  wall  of  the  gut.  In  this  case  the  contraction 
above  and  the  inhibition  below  cause  an  onward  movement 


142  THE    PHYSIOLOGY    OF    DIGESTION. 

of  the  bolus,  which  travels  slowly  down  the  whole  length 
of  the  gilt  until  it  passes  through  the  ileo-csecal  opening  into 
the  large  intestine.  The  peristaltic  contraction  involves,  as  I 
have  mentioned  before,  the  co-operation  of  a  nervous  system. 
Whereas  in  the  oesophagus  it  was  the  central  nervous  system 
which  was  involved,  the  peristaltic  contractions  in  the  small 
intestine  occur  after  severance  of  all  connection  with  the  brain 
and  spinal  cord.  On  the  other  hand,  it  is  absolutely  abolished 
by  painting  the  intestine  with  nicotine  or  with  cocaine.  It 
must  therefore  be  ascribed  to  the  local  nervous  system  con- 
tained in  Auerbach's  plexus,  which  we  can  regard  as  a  lowdy 
organised  nervous  system  with  practically  one  reaction, 
namely,  that  which  w^e  have  formulated  above  as  the  '  law  of 
the  intestines.'  An  anti-peristalsis  is  never  observed  in  the 
•small  intestine.  Mall  *  has  shown  that,  if  a  short  length  of  gut 
be  cut  out  and  re-inserted  in  the  opposite  direction,  a  species 
.of  partial  obstruction  results,  in  consequence  of  the  fact  that 
the  peristaltic  waves,  started  above  the  point  of  operation, 
.cannot  travel  downwards  over  the  reversed  length  of  gut. 
The  intestine  above  this  point  therefore  becomes  dilated.  If, 
however,  the  reactions  of  the  local  nervous  system  be  paralysed 
.or  inhibited,  a  reflux  of  intestinal  contents  is  quite  possible, 
: since  the  contractions  excited  at  any  spot  by  local  stimula- 
tion of  the  muscle  have  the  effect  of  driving  the  food  either 
upwards  or  downwards;  the  direction  of  movement  of  the 
food  will  be  that  of  least  resistance. 

The  movements  of  the  small  intestine  are  also  subject  to 
the  central  nervous  system.  Stimulation  of  the  vagus  has  the 
effect  of  producing  an  initial  inhibition  of  the  whole  small 
intestine,  followed  by  increased  irritability  and  increased  con- 
tractions.    On  the  other  hand,  stimulation  of  the  splanchnic 


*  Johns  Hophins  Hospital  Eeports,  Vol.  I.  p.  37,  1896. 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TRACT.  143 

nerves  causes  complete  relaxation  of  both  coats  of  the  small 
gut.  It  seems  that  the  splanchnics  normally  exercise  a  tonic 
inhibitory  influence  on  the  intestinal  movements,  which  can 
be  increased  by  all  manner  of  peripheral  stimuli.  On  this 
account  it  is  often  impossible  to  obtain  any  movements  in 
the  exposed  intestine,  so  long  as  these  remain  in  connection 
with  the  central  nervous  system  through  the  splanchnic 
nerves.  The  relaxed  condition  of  the  gut,  w^hich  obtains  in 
many  abdominal  affections,  is  probably  also  reflex  in  origin, 
and  is  due  to  reflex  inhibition  through  the  splanchnic  nerves. 
As  a  result  of  the  two  sets  of  movements  described  above, 
the  food  is  thoroughly  mixed  with  the  digestive  juices,  and  the 
greater  part  of  the  products  of  digestion  are  brought  into  con- 
tact with  the  intestinal  wall  and  absorbed.  What  is  left — a 
proportion  varying  in  dift'erent  animals  according  to  the 
nature  of  the  food — is  passed  on  by  occasional  peristaltic  con- 
tractions through  the  lower  end  of  the  ileum  into  the  colon, 
or  large  intestine.  The  lowest  two  centimetres  of  the  ileum 
present  a  distinct  thickening  of  its  circular  muscular  coat 
forming  the  ileo-colic  sphincter.  This  sphincter  relaxes  in 
front  of  a  peristaltic  w^ave  and  so  allows  the  passage  of  food 
into  the  colon.  On  the  other  hand,  it  contracts  as  a  rule 
against  any  regurgitation  which  might  be  caused  by  contrac- 
tions in  the  colon.  Although  thus  falling  into  line  wdth  the 
rest  of  the  muscular  coat,  as  concerns  its  reaction  to  stimuli 
arising  in  the  gut  above  or  below,  it  presents  a  marked  con- 
trast to  the  rest  of  the  gut  in  its  relation  to  the  central 
nervous  system.  It  is  apparently  unaffected  by  stimulation 
of  the  vagus.  Stimulation  of  the  splanchnic  however,  which 
causes  complete  relaxation  of  the  lower  part  of  the  ileum  with 
the  rest  of  the  small  intestine,  produces  a  strong  contraction 
of  the  muscle  fibres  forming  the  ileo-colic  sphincter. 


144  THE    PHYSIOLOGY    OF    DIGESTION. 

MOVEMENTS    OF    THE    LARGE    INTESTINE. 

By  means  of  the  occasional  peristaltic  contractions,  accom- 
panied by  relaxation  of  the  ileo-colic  sphincter,  the  contents 
of  the  small  intestine  are  gradaally  transferred  into  the  large. 

In  man,  these  contents  are  considerable  in  bulk,  are  semi- 
fluid, and  probably  fill  the  ascending  as  well  as  the  transverse 
colon. 

The  large  intestine  is  su]3plied  with  nerves  from  the  central 
nervous  system.  These  run  partly  in  the  sj^mpathetic  system 
along  the  colonic  and  inferior  mesenteric  nerves,  partly  in  the 
pelvic  ^dsceral  nerves  or  nervi  erigentes,  which  come  off  from 
the  sacral  cord  and  pass  direct  to  the  pelvic  viscera.  In 
addition  it  possesses  a  local  nervous  system,  presenting  the 
same  structure  as  that  found  in  the  small  intestine.  The 
movements  of  the  large  intestine  differ  considerably  in  various 
animals,  as  has  been  shown  by  Elliott,  according  to  the 
nature  of  the  food  and  the  part  played  by  this  portion  of  the 
gut  in  the  processes  of  absorption.  In  the  dog  the  process  of 
absorption  is  almost  complete  at  the  ileo-colic  valve,  whereas 
in  the  herbivora  a  very  large  part  of  the  processes  of  digestion 
and  absorption  occurs  in  the  colon  and  caecum.  Man  takes 
an  intermediate  position  as  regards  his  large  intestine  betw^een 
these  two  groups  of  animals.  Bayliss  and  I,  working  on  dogs, 
were  able  to  demonstrate  a  local  reaction  in  the  large  gut 
similar  to  that  we  had  described  in  the  small.  Elliott  *  has 
shown  however  that,  if  one  considers  a  number  of  different 
animals,  one  must  divide  the  large  intestine  into  four  parts, 
according  to  their  functions,  viz.,  the  caecum,  and  the  proximal, 
intermediate  and  distal  portions  of  the  colon.     Of  these  the 


*  Elliott  and  Barclay- Smith,  Joiirn.  of  Physiol.  Vol.  XXXI.  p.  272, 
1904. 


THE    MOVEMENTS    OF    THE    ALIMENTARY    TRACT.  145 

dog  possesses  practically  only  the  distal  colon.     We  may  take 
Elliott's  account  of  the  movements  as  they  probably  occur  in 
man.     They  agree  very  closely  with  those  observed  by  Cannon 
under  normal   circumstances   in   the   cat,  by  means  of  the 
Eontgen  rays.     The  food  as  it  passes  from  the  ileum  first  fills 
up   the  proximal  colon.     The  effect  of   this  distension  is  to 
cause   a   contraction   of   the   muscular  wall   at  the  junction 
between  the  ascending  and  transverse  colon.     This  contrac- 
tion travels  slowly  over  the  tube  in   a   backward  direction 
towards  the  cascum,  and  is  qtiickly  succeeded  by  another,  so 
that  the  colon  may  present  at  the  same  time  several  of  these 
advancing  waves.      These  waves  are  spoken  of  as  anti-peri- 
staltic ;  but,  as  they  do  not  involve  also  an  advancing  wave  of 
inhibition,  they  must  not   be   regarded  as  representing  the 
exact  antithesis  of  a  peristaltic  wave,  as  we  have  defined  it. 
The  effect  of  these  waves  is  to  force  the  food  up  into   the 
caecum,  regurgitation  into  the  ileum  being  prevented  partly  by 
the  obliquity  of  the  opening,  partly  by  the  tonic  contraction 
of  the  ileo-colic  sphincter.    x\s  the  whole  of  the  contents  cannot 
escape  into  the  caecum,  a  certain  portion  will  slip  back  in  the 
axis  of  the  tube,  so  that  these  movements  have  the  same  effect 
as  the  similar  contractions  in  the  pyloric  end  of  the  stomach, 
causing  a  thorough  churning  up  of  the  contents  and  its  close 
contact  with  the  intestinal  wall.    The  movements  are  rendered 
still  more  effective  by  the  sacculation  of  the  walls  of  this  part 
of  the  large  intestine.     The  distension  of  the  caecum  caused 
by  this  anti-peristalsis  excites  occasionally  a  true  co-ordinated 
peristaltic  wave,  which,  starting  in  the  caecum,  drives  the  food 
down  the  intestine  into  the  transverse  part.     These  waves 
die  away  before  they  reach  the  end  of  the  colon,  and  the  food 
is  driven  back  again  by  waves  of  anti-peristalsis.    Occasionally 
more  food  escapes  through  the  ileo-colic  sphincter  from  the 
ileum,  so   that   the   whole   ascending   and   transverse   colon 

P.D.  L 


146  THE    PHYSIOLOGY    OF    DIGESTION. 

may  be  filled  with  the  mass  undergoing  a  constant  knead- 
ing and  mixing  process.  The  result  of  this  process  is  the 
absorption  of  the  greater  part  of  the  water  of  the  intestinal 
contents,  as  well  as  of  any  nutrient  material,  and  the  drier  part 
of  the  intestinal  mass  collects  towards  the  splenic  flexure, 
where  it  may  be  separated  by  transverse  waves  of  constriction 
from  the  more  fluid  parts  which  are  being  driven  to  and  fro 
in  the  proximal  and  intermediate  portions.  By  means  of 
occasional  peristaltic  waves  these  hard  masses  are  driven 
into  the  distal  part  of  the  colon.  The  distal  colon  must  be 
regarded  as  a  place  for  the  storage  of  the  faeces,  and  as  the 
organ  of  defecation.  In  the  transverse  colon,  in  the  descending 
and  ileo-colon,  the  anti-peristaltic  movements  and  consequent 
churning  of  the  contents  are  probably  slight.  These  therefore 
represent  the  intermediate  colon  with  propulsive  peristalsis  as 
its  chief  activity.  The  descending  colon  is  never  distended, 
and  Elliott  therefore  regarded  it  as  a  transferring  segment  of 
exaggerated  irritability.  The  storage  of  the  waste  matter 
takes  j)lace  chiefly  in  the  sigmoid  flexure.  This  with  the 
rectum  represents  the  distal  portion  of  the  colon.  The 
distinguishing  feature  of  the  distal  colon  is  its  complete 
subordination  to  the  spinal  centres.  It  probably  remains 
inactive  until  an  increasing  distension  excites  reflexly  through 
the  pelvic  visceral  nerves  a  complete  evacuation  of  this  portion 
of  the  gut.  Stimulation  of  these  nerves  in  an  animal,  such  as 
the  cat,  produces  a  rapid  shortening  of  the  distal  part  of  the 
colon,  due  to  contraction  of  the  recto-coccygeus  and  longi- 
tudinal fibres  of  the  gut,  followed  after  some  seconds  by  a 
contraction  of  the  circular  coat.  This  originates  at  the  lower 
limit  of  the  area  of  anti-peristalsis,  i.e.,  probably  at  the  upper 
end  of  the  sigmoid  flexure,  and  spreading  rapidly  downwards, 
empties  the  whole  of  this  segment  of  the  gut.  In  man  the 
emptying  of  the  rectum  itself  is,  of  course,  largely  assisted 


THE    MOVEMENTS    OF    THE    ALIMENTArxY    TRACT.  147 

by  the  contractions  of  the  vohmtary  muscles  of  the  abdominal 
walls  and  pelvic  floor. 

^\e  see,  then,  that  the  "whole  of  the  movements  of  the 
alimentary  canal  are  completely  adapted  to  effect  the  digestion 
and  absorption  of  the  food-stuffs.  At  the  upper  and  lower 
ends  of  the  canal,  these  movements  are  under  the  direct 
control  of  the  central  nervous  system,  since  they  have  to  be 
guided  in  accordance  with  the  requirements  of  the  animal's 
environment.  In  the  middle  parts  of  the  gut,  where  the 
processes  of  digestion  and  absorption  must  go  on  without 
reference  to  the  external  conditions  or  activities  of  the  animal, 
the  movements  are  chiefly  determined  by  local  mechanisms. 
Even  here„  however,  they  can  be  completely  abolished, 
through  the  spinal  cord  and  sympathetic  system,  in  cases 
where  injury  of  the  abdominal  cavity  may  render  the  local 
acti\aties  dangerous  for  the  animal.  The  complete  paralysis 
of  the  gut,  which  has  been  observed  in  cases  of  gun-shot 
wound  of  the  abdomen,  is  probably  protective  in  function  and 
determined  by  splanchnic  stimulation. 

The  motor  activities  of  the  alimentary  canal  present  an 
ordered  march  of  events  as  suited  to  the  needs  of  the  organism 
as  are  those  which  we  have  studied  in  dealing  with  the  secre- 
tion of  the  digestive  fluids.  They  differ  from  these  in  being 
more  rapidly  adaptable,  and  are  therefore  determined  entirely 
by  nervous  mechanisms.  So  far  as  we  know,  chemical 
mechanisms  play  no  part  in  the  muscular  activities  of  any 
part  of  the  alimentary  canal. 


APPENDIX 


LIST    OF    PAPEES, 

Bearing  on  the  Subjects  treated  of  in  the  lyreceding  Lectures, 
ichich  have  been  inthlishcd  since  1899  by  Workers  in  the 
Physiological  Department,   University  College. 


LECTUEE   I. 

(1)  "  Some  Eesearches  on  the  Autolytic  Degradation  of  Tissues." 

Pt.  I.     By  Janet  E.  Lane-Claypon,  B.Sc,  and  S.  B.  Scbryver, 
D.Sc.     {Journ.  of  Physiol,  Vol.  XXXL,  1904.) 

(2)  "Eesearches  on  the  Autolytic  Degradation  of  Tissues."     By 

S.  B.   Schryver.     Pt.  II.     (Journ.  of  Physiol,  Vol.  XXXII., 
1905.) 

LECTUEE    IL 

(3)  "  The  Kinetics  of  Tryptic  Action."     By  W.  M.  BayHss,  F.E.S. 

{Archives  des  Sciences  Biol,  Vol.  XL,  Suplt.    St.  Petersburg, 
1901) 

(4)  "The   Effect   of   Electrolytes   on    Adsorption."     By   W.   M. 
Bayliss.     {Biochemical  Journal,  Vol.  I.,  1906.) 

(5)  "  The    Separation    of    Phosphorus   from   Caseinogen   by   the 

Action  of  Enzymes  and  Alkali."  By  E.  H.  Aders  Plimmer, 
D.Sc,  and  W.  M.  Bayhss,  F.E.S.  {Journ.  of  Physiol,  Vol. 
XXXIII.,  p.  439,  1906.) 


150     ♦  APPENDIX. 


LECTUEB    III. 


(6)  "  On  the  Changes  in  Yohime  of  the  Submaxillary  Gland 
during  Activity."  By  J.  Le  M.  Bunch,  D.Sc,  M.D.  {Journ. 
of  Physiol,  Vol.  XXVI.,  1900.) 

(7)  "  Observations  on  the  Lymph  Flov^  from  the  Submaxillary 
Gland  of  the  Dog."  By  F.  A.  Bainbridge,  B.A.,  B.Sc. 
{Journ.  of  Physiol,  Vol.  XXVI.,  1900.) 

LECTUEE    V. 

(8)  "  On  the  Causation  of  the  so-called  '  Peripheral  Eeflex  Secre- 
tion' of  the  Pancreas."  (Preliminary  communication.)  By 
W.  M.  Bayliss  and E.  H.  Starling.  {Proc.  Boy.  Soc,  January  23, 
1902.) 

(9)  "  The  Mechanism  of  Pancreatic  Secretion."  By  W.  M. 
Bayliss  and  E.  H.  Starling.  {Journ.  of  Physiol,  Vol. 
XXVIII.,  1902.) 

(10)  "  On  the  Uniformity  of  the  Pancreatic  Mechanism  in  Verte- 
brata."  By  W.  M.  Bayhss  and  E.  H.  Starling.  {Journ.  of 
Physiol,  Vol.  XXIX.,  1903.) 

(11)  **  On  some  Pathological  Aspects  of  Eecent  Work  on  the 
Pancreas."  By  E.  H.  Starling.  {Trans,  of  Path.  Soc.  of 
London,  Vol.  LIV.,  1903.) 

(12)  Croonian  Lecture  (Eoyal  Society)  on  "  The  Chemical  Eegu- 
lation  of  the  Secretory  Process."  By  W.  M.  Bayliss  and 
E.  H.  Starling.      {Proc.  Boy.  Soc,  Vol.  LXXIIL,  1904.) 

LECTUEE    VI. 

(13)  "The  'Islets  of  Langerhans'  in  the  Pancreas."  By  H.  H. 
Dale,  B.Ch.  (Proc.  Boy.  Soc,  Vol.  LXXIII.,  1904,  and  Phil 
Trans.  Boy.  Soc,  Series  B,  Vol.  CXCVII.,  1904.) 

(14)  "  The  Oxygen  Exchange  of  the  Pancreas."  By  J.  Barcroft 
and  E.  H.  Starling.      {Jo2trn.  of  Physiol,  Vol.  XXXL,  1904.) 

(15)  "The  Lymph  Flow  from  the  Pancreas."  By  F.  A.  Bain- 
bridge, M.D.     {Journ.  of  Physiol,  Vol.  XXXIL,  1904.) 


APPENDIX.  151 

LECTUKE    VII. 

(16)  "  On  the  Composition  of  the  Pancreatic  Juice."  By  L. 
A.  E.  de  Zilwa,  M.B.    {Joum.  of  Physiol,  Vol.  XXXI.,  1904.) 

(17)  "  The  Proteolytic  Activities  of  the  Pancreatic  Juice."  By 
W.  M.  Bayhss  and  E.  H.  Starhng.  {Joum.  of  Physiol, 
Vol.  XXX.,  1903.) 

(18)  "On  the  Eelation  of  Enterokinase  to  Trypsin."  By  W.  M. 
Bayliss  and  E.  H.  Starling.  {Joum.  of  Physiol,  Vol.  XXXII., 
1905.) 

(19)  '*  On  the  Adaptation  of  the  Pancreas  to  Different  Food-stuffs." 
(Prehminary  communication.)  By  F.  A.  Bainbridge.  {Proc. 
Boy.  Soc,  Vol.  LXXII.,  1903.) 

(20)  "  On  the  Adaptation  of  the  Pancreas."  By  F.  A.  Bainbridge. 
{Joum.  of  Physiol,  Vol.  XXXI. ,  1904.) 

(21)  "On  the  Alleged  Adaptation  of  the  Pancreas  to  Lactose." 
By  E.  H.  Aders  Plimmer,  D.Sc.  {Joum.  of  Physiol,  Vol. 
XXXIV.,  1906.) 

(22)  "  On  the  Identity  of  Trypsinogen  and  Enterokinase  respec- 
tively in  Vertebrates."  By  J.  Molyneux  Hamill,  M.A.,  M.B. 
{Joum.  of  Physiol,  Vol.  XXXIII.,  1906.) 

(23)  "  On  the  Mechanism  of  Protection  of  Intestinal  Worms,  and 
its  Bearing  on  the  Eelation  of  Enterokinase  to  Trypsin."  By 
J.  M.  Hamill.     {Joum.  of  Physiol,  Vol.  XXXIII.,  1906.) 

LECTUEE    VIII. 

(24)  For  "  Action  of  Secretin  on  Bile  "  v.  Paper  No.  (9)  in  Joum. 
of  Physiol,  Vol.  XXVIIL,  1902. 

(25)  "  The  Contractile  Mechanism  of  the  Gall  Bladder  and  its 
Extrinsic  Nervous  Control."  By  F.  A.  Bainbridge  and 
H.  H.  Dale.     {Joum.  of  Physiol,  Vol.  XXXIII.,  1905.) 

(26)  "  A  Note  on  Hiifner's  Method  of  Preparing  Pure  Glycocholic 
Acid."     By  W.  A.  Osborne.     {Proc.  Physiol  Soc,  1900.) 

(27)  "On  the  Formation  of  Lymph  by  the  Liver."  By  F.  A. 
Bainbridge.     {Joum.  of  Physiol,  Vol.  XXVIIL,  1902.) 


152  APPENDIX. 

LECTUEE    IX. 

(28)  "The  Presence  of  Lactose  in  Animals."  By  B.  H.  Aders 
Plimmer.     {Proc.  Physiol.  Soc,  1906.) 

(29)  Croonian  Lectures  given  at  the  Eoyal  College  of  Physicians, 
London,  "  On  the  Chemical  Correlation  of  the  Functions 
of  the  Body."  By  E.  H.  Starhng.  (Published  in  Lancet, 
August,  1905.) 

LECTUEE    X. 

(30)  "The  Movements  and  Innervation  of  the  Small  Intestine." 
Pt.  I.  By  W.  M.  Bayliss  and  E.  H.  Starling.  {Journ.  of 
Physiol,  Vol.  XXIV.,  1899.) 

(31)  Idem.  Pts.  11.  and  III.  [Journ.  of  Physiol,  Vol.  XXVL, 
1901.) 

(32)  "  The  Movements  and  Innervation  of  the  Large  Intestine." 
By  W,  M.  Bayhss  and  E.  H.  Starhng.  {Journ.  of  Physiol, 
Vol.  XXVI.,  1901.) 

(33)  "  On  the  Movements  and  Innervation  of  the  Stomach."  By 
W.  Page  May,  M.D.     {Brit  Med.  Journ.,  Sept.  13,  1902.) 

(34)  "The  Innervation  of  the  Sphincters  and  Musculature  of  the 
Stomach."  By  W.  Page  May.  {Journ.  of  Physiol,  Vol. 
XXXI.,  1901.) 


INDEX. 


Active  mass,  28. 
Adaptation  of  pancreas,  108. 

of  stomach  to  food,  77. 

Adrenalin,  1)1,  130. 
Adsorption,  15. 

of  dyes,  38. 

of  toxins  by  antitoxins,  38. 

Asi'glutination  of  bacilli,  3(5. 
Alimentary  tract,  movements  of,  129 

— U7. 
Amide-nitrogen,  G. 
Araino-acids,  6,  9. 
Amylase,  9,  104. 

of  saliva,  42. 

Antikinase,  107. 

Antilysin,  34. 

Antiperistalsis  in  colon,  145. 

Antitoxin,  34. 

Antitrypsin,  107. 

Armstrong,  experiments  on  lactase,  25. 

Arrhenius,  on  toxins  and    antitoxins 

37. 
Atropin,  effect  on  salivary  secretion, 

48. 
Auerbach's  plexus,  function  of,  142. 


Bainbridge,  on  lactase,  110. 

on  lymph  flow  from  sali- 
vary glands,  51. 
Barcroft,    on    gaseous    exchanges    of 
pancreas,  95. 

on  salivary  glands,  50. 

Bayliss,  on  intestinal  ferments,  127. 

on   movements   of  intestines, 

139,  144. 

on  action  of  trypsin,  24. 


Bernard,  on  pancreatic  fistula,  81. 
Bile,  112—119. 

analyses  of,  113. 

digestive  functions  of,  1  Kl. 

pigments,  113. 

salts,  function  of,  117. 

Biliary  fistula,  114. 

Bredig,  on  preparation  of  sols,  39. 

Bunch,  on  salivary  glands,  52. 


Calorie,  definition  of,  2. 
Cannon,  on  movements  of  intestines, 
137. 

on  movements  of    stomach, 

134. 
Carbohydrates,  2. 

digestion  of.  9. 

Caseinogen,  digestion  of,  24. 
Catalysers  (catalysts),  11. 

specificity  of,  13. 

Catalytic  action  of  sols,  40. 
Chemical  correlation,  88. 
Chorda  tympani,  44. 
Colloidal  solutions,  15. 
Colon,  movements  of,  144. 
Craw,   on   interaction  of   toxins  and 
antitoxins,  3(). 


Dakin,  on  lipase,  32. 
Dale,  on  gall-bladder,  115. 

on  islets  of  Langerbans,  98. 

Dastre,  on  enterokinase,  105. 

Defaecation,  14^. 

Deglutition,  131. 

De  Graaf,  on  pancreatic  fistula,  80. 


154 


INDEX. 


Delezenne,  on  enteroldnase,  105. 

Diabetes,  relation  to  pancreas,  98. 

Diamino-acids,  6,  10. 

Diastase,  velocity  of  reaction,  22. 

Diet,  2. 

Digestion  in  the  stomach,  62 — 79. 


Edkins,  on  gastric  secretion,  74. 

Ehrlich's  theory  of  htemolysins,  34. 

Elliott,  on  movements  of  large  intes- 
tine, 144. 

Emulsin,  31. 

Energy  of  food-stufEs,  3. 
of  salivarj^  secretion,  49,  58. 

Enterokinase,  104. 

origin  of,  107. 

Equation  of  reaction,  21. 

Erepsin,  9,  103,  126. 


Falloise,  on  intestinal  ferments,  127. 

on  intestinal  secretion,  122. 

Fats,  absorption  of,  118. 

composition  of,  2. 

digestion  of,  9,  116. 

Ferments,  action  of,  8,  14. 

autodestruction  of,  28. 

chemical  composition  of,  33. 

— - — ■       colloidal  nature  of,  33. 

combination  with  substrate, 

31,  39. 

effect  of  bile  on,  116. 

effects  of  concentration  of, 

24. 

mode  of  action  of,  10 — 40. 

optical  activity  of,  32. 

retarding  effect  of  end-pro- 

ducts, 30. 

reverse  action  of,  30. 

specificity  of,  12,  31. 

of  alimentary  canal,  8. 

■ of  intestinal  juice,  126. 

of  pancreatic  juice,  103. 

Fleig,  on  secretin,  92. 
Food-stuffs,  absorption  of,  128. 

changes  during  digestion, 

1—10. 

classification  of,  2. 


Food-stuffs,  digestion  of,  8. 

effect  on'  biliary  secretion, 

119. 
— —        heat  value  of,  2. 


Gall-bladder,  movements  of,  115. 
Gaseous  exchanges  of  pancreas,  95. 

of  salivary  glands, 

58. 
Gastric  fistula,  64. 

juice,  properties  of,  67. 

secretion  of,  62,  6Q. 

secretion,  chem^ical  mechanism 

of,"  74. 

effect  of  quality  of 

food  on,  76. 

nervous    mechanism 

of,  69. 


Glands,  changes  during  secretion,  54. 

of  stomach,  62. 

Glucose,  oxidation  of,  16. 
Glucosides,  action  of  ferments  on,  31. 
Granules  of  pancreas,  97. 

of  salivary  glands,  56.. 


Hgemolysins,  34. 

Hamill.  on  antitrypsin,  107. 

Haptophore,  35. 

Heat  production  in   salivary  glahds, 

59. 
Hormone,  gastric,  75. 
Hormones,  chemical  nature  of,  91. 

definition  of,  90. 

for  intestinal  secretion,.  124. 

Hydrochloric      acid,      secretion      by 

stomach,  64. 
Hydrogen  peroxide,  catalysis  of,  11. 
Hydrolysis  of  food-stuffs,  10. 


Ileocolic  sphincter,  143. 
Indigo,  effect  on  glucose,  16. 
Inhibition,  131. 

in  intestine,  141. 

Intermediate  products,  16. 
Intestinal  fistula,  121. 

juice,  120—128. 


INDEX. 


155 


Intestinal  juice,  characters  of,  125, 
Intestine,  distribution  of  prosecretin 
in,  88. 

law  of,  141. 

•       local  reflexes  of,  125. 

movements  of,  137 — 143, 

large,  movements  of,  l-ll — 

147. 
Invertase,  9,  12,  126. 

chemical  composition  of,  33. 

velocity  of  reaction,  22, 

Islets  of  Langerhans,  98. 

formation  during 

activity,  100. 

Lactase,  9,  12,  25,  110,  126. 
Laguesse,  on  islets  of  Langerhans,  101. 
Langley,  on  secretory  nerves,  46. 
Lipase,  9,  32,  104. 

solution  of,  117. 

Ludwig,  on  salivary  glands,  48. 
Lymph  flow  from  salivary  glands,  51. 

production  in  salivary  glands, 

60. 
Lysin,  34. 

Magnus,  on  intestinal  movements,  139. 
Mall,  on  reversal  of  gut,  142. 
Maltase,  9,  12,  126. 
Mammary  glands,  growth  of,  91, 
Mandelic  acid,  32. 

Mendel,  on  intestinal  secretion,  122. 
Molybdic  acid,  catalytic  action  of,  18. 
Moreau,  on  intestinal  secretion,  122. 
Movements  of  alimentary  tract,  129 — 
147. 

Nervi  erigentes,  effect  on  colon,  144. 

Nervous  mechanism  of  intestinal  secre- 
tion, 122. 

Nitrogen,  condition  in  proteid  mole- 
cule, 6. 

Nitrogenous  derivatives  of  proteids,  9. 

(Esophagus,  movements  of,  131. 
Optimum    temperature     of     ferment 

action,  13. 
Osborne,  on  invertase,  33. 
Osmotic  pressure  of  saliva,  47. 


Oxygen  carrier,  17. 

requirements 

glands,  58. 
Oxyntic  cells,  63. 


of       salivary 


Pancreas,   changes   during    secretion, 
94—101. 

histology  of,  96. 

normal  stimulation  of,  92. 

Pancreatic  fistula,  80. 

juice,  alkalinity  of,  102. 

properties  of,   102— 

111. 

qualitative      adapta- 

tion of,  108. 

time      relations      of 

secretion  of,  83. 

secretion,  80 — 93. 

chemical   mecha- 

nism of,  86. 
Parietal  cells,  63. 

Pawlow,  on  adaptation   of  pancreas, 
108. 

on  biliary  fistula,  114. 

on  division  of  vagi,  136. 

on  enterokinase,  105. 

on  gastric  fistula,  64. 

on  intestinal  secretion,  1 23. 

on  pancreatic  fistula,  81. 

on  secretion  of  saliva,  43. 

Pendular  movements,  138. 
Pepsin,  8. 

secretion  of,  64. 

separation  of,  68. 

Peptic  cells,  63. 
Peptogenic  substances,  73. 
Peristalsis,  definition  of,  131. 

of  small  intestine,  140. 

of  large  intestine,  145. 

Platinum,  catalytic  effect  of,  11. 

•      nature  of    catalytic  action 

of,  17. 
Plimmer,  on  lactase,  110. 
Popielski,  on  gastric  juice,  76. 

on  pancreatic  secretion,  85. 

Prosecretin,  88. 

Proteid,  significance  as  food-stuff,  3. 
Proteids,  2. 

constitution  of,  6. 


156 


INDEX. 


Proteids,  digestion  of,  9. 

effect  of  gastric  iuice  on,  67. 

effect  on  excretion,  3. 

Proteolysis,    change    of    conductivity 

during,  24. 

Proteolytic  ferments,   velocity  of  re- 
action, 23. 

Protoplasm,  building  up  of,  6. 

Psychical  secretion  of  gastric  juice,  69. 

Ptyalin,  42. 

Pylorus,  movements  of,  137. 

Eeaction,  modes  of  studying  velocity 
of,  22. 

velocity  of,  11,  20. 

Reactions,  bimolecular,  21. 

monomolecular,  21. 

reversible,  29. 

Keflex  secretion  of  pancreatic  juice,  84. 
Kennin,  36. 
Revertose,  30. 

Saliva,  composition  of,  41. 

functions  of,  42, 

molecular  concentration  of,  47. 

secretion  of,  41 — 61. 

Salivary  glands,  changes  during  secre- 
tion, 53. 

nerves  of,  44. 

Sapocrinin,  92. 

Secretin,  effect  on  bile,  115. 

intestinal  secretion, 

123. 

■ structure    of    pan- 

creas, 97. 

gastric,  75. 

pancreatic,  87. 

Secretion  of  intestinal  juice,  121. 

• of  saliva,  41 — 61. 

mechanism  of,  45,  59. 

pancreatic,  80 — 93. 

psychical,  of  saliva,  43. 

Secreto-motor  nerves,  46. 
Secretory  nerves  to  pancreas,  84. 

to  stomach,  70. 

pressure,  48. 

of  pancreas,  94. 


Sol,  40. 

Splanchnic  nerve,  effects  on  intestinal 

movements,  143. 
Steapsin,  9. 
Stomach,  digestion  in,  62 — 79. 

movements  of,  79,  133 — 137. 

mucous  membrane  of,  62. 

Substrate,  19. 

combination  with  ferments, 

31. 

effect  of    concentration  of, 

26. 
Succus  entericus,  120 — 128. 
Sugars,  assimilation  of,  127. 
Surface,  effects  of,  15. 
Sympathetic  saliva,  45. 

Temperature,  effect  on  ferment  action, 

14. 
Toxin,  neutralisation  of,  36. 
Toxins,  34. 
Toxoids,  35. 
Toxones,  37. 
Toxophore,  35. 
Transverse  band,  134. 
Trophic    nerves    of    salivary   glands, 

46. 
Trypsin,  8,  104. 

modification  by  heat,  35. 

reaction,  velocity  of,  27. 

velocity  of  action,  23. 

Trypsinogen,  104. 

relation  to  enterokinase, 

105. 

Vagus,  effect  on  gastric  secretion,  70. 

intestinal  movements, 

142. 

oesophagus,  132 

gastric      movements, 

136. 
Velocity  constant,  21. 

Weinland,  on  antitrypsin,  107. 

on  lactase,  109. 

Wertheimer,  on  pancreatic  secretion, 
85. 


Serdjukow,  on  contraction  of  pylorus, 
137. 


Zymoids,  35. 

BRADBURY,   AGNEW,   &  CO.    LD.,   PRINTERS,    LONDON   ANH  TONBRIDGE. 


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